Next Article in Journal
Blood Oxidative Stress Modulates Alveolar Bone Loss in Chronically Stressed Rats
Next Article in Special Issue
Cellular Mechanisms of Circulating Tumor Cells During Breast Cancer Metastasis
Previous Article in Journal
CRISPR-Cas9-Based Mutagenesis of the Mucormycosis-Causing Fungus Lichtheimia corymbifera
Previous Article in Special Issue
Colorectal Cancer Invasion and Atrophy of the Enteric Nervous System: Potential Feedback and Impact on Cancer Progression
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
IJMS
Volume 21
Issue 10
10.3390/ijms21103726
ijms-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Mechanisms of Apoptosis Resistance to NK Cell-Mediated Cytotoxicity in Cancer

by
Christian Sordo-Bahamonde
1,2,3,*,†,
Seila Lorenzo-Herrero
1,2,3,†,
Ángel R. Payer
2,3,4,
Segundo Gonzalez
1,2,3 and
Alejandro López-Soto
2,3,5,*
1
Department of Functional Biology, Immunology, University of Oviedo, 33006 Oviedo, Spain
2
Instituto Universitario de Oncología del Principado de Asturias, IUOPA, 33006 Oviedo, Spain
3
Instituto de Investigación Biosanitaria del Principado de Asturias (ISPA), 33011 Oviedo, Spain
4
Department of Hematology, Hospital Universitario Central de Asturias (HUCA), 33011 Oviedo, Spain
5
Department of Biochemistry and Molecular Biology, University of Oviedo, 33006 Oviedo, Spain
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally.
Int. J. Mol. Sci. 2020, 21(10), 3726; https://doi.org/10.3390/ijms21103726
Submission received: 21 April 2020 / Revised: 20 May 2020 / Accepted: 22 May 2020 / Published: 25 May 2020
(This article belongs to the Special Issue Survival Pathways Involved in Resistance to Apoptosis in Cancer)
Browse Figure
Versions Notes

Abstract

:
Natural killer (NK) cells are major contributors to immunosurveillance and control of tumor development by inducing apoptosis of malignant cells. Among the main mechanisms involved in NK cell-mediated cytotoxicity, the death receptor pathway and the release of granules containing perforin/granzymes stand out due to their efficacy in eliminating tumor cells. However, accumulated evidence suggest a profound immune suppression in the context of tumor progression affecting effector cells, such as NK cells, leading to decreased cytotoxicity. This diminished capability, together with the development of resistance to apoptosis by cancer cells, favor the loss of immunogenicity and promote immunosuppression, thus partially inducing NK cell-mediated killing resistance. Altered expression patterns of pro- and anti-apoptotic proteins along with genetic background comprise the main mechanisms of resistance to NK cell-related apoptosis. Herein, we summarize the main effector cytotoxic mechanisms against tumor cells, as well as the major resistance strategies acquired by tumor cells that hamper the extrinsic and intrinsic apoptotic pathways related to NK cell-mediated killing.

1. Introduction

Natural killer (NK) cells are large granular innate lymphoid cells. This immune subset is in charge of recognizing and eliminating viral-infected and tumor-transformed cells in an antigen-independent manner, playing a key role in the immune control of tumor development and metastasis [1,2,3]. Whereas cytotoxic T lymphocyte stimulation is antigen-specific dependent, NK cell activation relies on their ability to discern infected and malignantly transformed cells without any prior sensitization [1,4,5].
During NK cell ontogenesis, these innate immune cells undergo a “licensing” process whereby cells expressing major histocompatibility complex class I (MHC-I) self-specific inhibitory receptors are positively selected, acquiring functional competence. Thereby, NK cells lacking MHC-specific inhibitory receptors do not achieve functional maturation [4]. According to the missing-self hypothesis, MHC-I recognition by inhibitory receptors prevents NK cell-mediated cytotoxic activity against healthy cells. This regulation of NK cell function is mainly mediated by Killer Immunoglobulin Receptors (KIRs/CD158 family), C-type lectin receptors (CD94/NK group 2 member A, NKG2A), and leukocyte immunoglobulin-like receptor-1 (LILRB1/ILT2) [6,7].
NK cell activation is closely controlled by a precise balance between the signals provided by these inhibitory and stimulatory receptors [1]. The sum of these opposing signals determines the activation status of the NK cell, playing a crucial role in maintaining self-tolerance and limiting immune responses, which, in turn, prevents autoimmunity. NK cells recognize the increased expression of stress-induced molecules on the surface of viral-infected or cancer cells by activating receptors, such as activating receptor killer cell lectin like receptor K1 (KLRK1/NKG2D), DNAX accessory molecule 1 (DNAM-1), and the natural cytotoxicity receptors natural killer P30, 44, and 46 (NKp30, NKp44, and NKp46) [8]. In humans, NKG2D stress-induced ligands include MHC class I polypeptide-related sequence A and B (MICA and MICB) and UL16 binding proteins (ULBPs). Additionally, NK cells may also eliminate target cells which are opsonized by antibodies via engagement of Fc gamma receptor CD16 in an antibody-dependent cellular cytotoxicity (ADCC).
Upon target cell recognition, NK cells may mediate target cell lysis via direct release of lytic granules or engagement of death receptor-related apoptosis through tumor necrosis factor (TNF), Fas ligand (FasL), and TNF-related apoptosis-inducing ligand (TRAIL) production, whose surface receptors are commonly expressed by tumor cells [9]. These killing mechanisms trigger certain programmed intracellular events on target cells and constitute the biological basis of a variety of approaches employed in cancer immunotherapy, such as ADCC in the treatment of hematological malignancies (i.e., rituximab in B-cell malignancies) and solid tumors (i.e., cetuximab in head and neck cancers) [10,11,12,13,14]. However, the ultimate mechanisms that lead to tumor cell death upon exposure to immunotherapeutic treatments remains unclear. Altogether, the cytotoxic capacity of NK cells highlights the importance of this immune subset in promoting apoptosis and eliminating cancer cells. Activation of programmed cell death signaling appears to be a central player in preventing tumor progression, since resistance to apoptosis has been defined as a hallmark of cancer [15].
In this context, two main mechanisms are responsible for NK cell-mediated cytotoxicity resistance: 1) tumor cells take advantage of co-inhibitory signaling to avoid NK cell-mediated responses, leading this immune subset to an anergic or irresponsiveness state, and 2) tumor cells avoid NK cell effector activity after target cell recognition (i.e., inefficient perforin (PRF1) binding).
Further, diverse strategies conferring apoptotic resistance are present in all types of cancers, affecting both the intrinsic (via mitochondria) and extrinsic (mediated by death receptors) pathways. These include, but are not limited to, BCL2 overexpression, mutation/deletion of the TP53 gene, as well as caspase activity dysfunction [16]. In this review, we summarize the major mechanisms affecting NK cell-mediated apoptosis and resistance in cancer.

2. NK Cell-Killing Mechanisms

2.1. NK Cell Killing Mechanisms: Death Receptors, the Extrinsic Apoptosis Pathway

The extrinsic apoptotic pathway is initiated when the so-called death ligands bind to their cognate TNF-family death receptors, promoting caspase-dependent apoptotic cell death. To date, nine different receptors have been described (Table 1).
Fas/CD95 is a membrane-bound receptor ubiquitously expressed in humans, whereas its cognate ligand (FasL/CD95L) is mainly expressed by NK cells and cytotoxic T lymphocytes [17]. Upon receptor-ligand recognition, the extrinsic apoptotic pathway is activated by a Fas death domain. This cell surface receptor modulates immune system homeostasis, limiting immune responses and promoting the elimination of malignant cells [18]. TRAIL is a type II transmembrane protein that, as with most of the TNF family members, forms homotrimers that bind to three receptor molecules [19]. TRAIL expression may be detected on immune cells from myeloid and lymphoid origin, but, interestingly, peripheral blood NK cells do not express membrane TRAIL and yet, it is constitutively expressed on liver NK cells in humans [20,21]. Nonetheless, surface expression of this molecule is upregulated on NK cells upon activation by cytokines, such as IL-15 and IFN-γ, bringing about NK cell-mediated target cell apoptosis [20].
Despite the fact that TRAIL may bind to five different receptors, only TRAIL-R1 and TRAIL-R2 are capable of inducing extrinsic apoptotic cell death through their death domain (Table 1) [22]. No death domain is present in TRAIL-R3, TRAIL-R4, or osteoprotegerin, so receptor-ligand binding does not induce caspase recruitment and activation [23]. These “decoy” receptors are in charge of protecting cells from apoptosis by competing with death receptors for TRAIL binding, activating pro-survival signaling pathways such as NF-kB (nuclear factor-κB), and forming inactive complexes with TRAIL-R2 [24,25,26,27,28].
Binding of death receptors (such as TRAIL-R1/R2 or Fas) to their respective ligands induces receptor oligomerization and, subsequently, the death domain attracts the adaptor proteins FADD (Fas-associated with death domain protein) and TRADD (TNF receptor-associated death domain) (Figure 1) [22,29]. This event initializes the recruitment of inactive proforms of procaspase-8 and procaspase-10, inducing the formation of the death-inducing signaling complex or DISC [29]. Once this complex is assembled, both procaspases are activated by cleavage, promoting the recruitment of executioner caspases (caspase-3, -6, and -7). This extrinsic signaling alone may not be enough to induce apoptosis and requires an amplification step induced by caspase-8, which targets the BH3-only protein Bid (BH3-interacting-domain death agonist), activating the intrinsic pathway [30,31]. Membrane bound forms of TRAIL and FasL exert optimal activity inducing cell death, whereas soluble forms of these proteins (cleaved by metalloproteases or cathepsin, respectively) poorly induce cell death or even exert tumor-promoting functions [32,33,34,35].
NK cells play a key role in the elimination of cancer cells and metastasis control, at least in part, due to FasL and TRAIL-mediated cell death [2,36]. Patients with autoimmune lymphoproliferative syndrome (ALPS), who bear mutations affecting FasL or caspase-10, show increased risk of Hodgkin (HL) and non-Hodgkin lymphoma (NHL), highlighting the importance of the extrinsic apoptosis pathway [37]. Further, Fas/FasL disruption in mice led to the spread of solid and hematologic tumors [38,39,40,41]. Accordingly, TRAIL-deficient mice displayed increased susceptibility to tumor development, including enhanced tumor growth in mice challenged with A20 B lymphoma cells [42]. Likewise, TRAIL−/− mice were observed to be more sensitive to experimental and spontaneous metastasis as well as those caused by chemical carcinogens in a wide variety of cancers [43,44,45,46,47].
Altogether, these data highlight the relevance of NK cell-mediated cytotoxicity in eliminating nascent and established tumors and limiting metastasis. In parallel, cancer cells have developed numerous mechanisms counteracting the extrinsic and intrinsic apoptotic pathways or taking advantage of its mediators (see Table 2).

2.2. NK Cell-Killing Mechanisms: Target Cell Lysis by Perforin, Granzymes and Granulysin Granules

In addition to activation of the death receptor pathway, exocytosis of cytotoxic granules with perforin (PRF1) and granzymes (GZMs) is a major mechanism of NK cell-induced apoptotic tumor cell death. This process involves target cell recognition by the mechanisms described above (including ADCC), followed by formation of the immunological synapse via integrin-mediated adhesion, and mobilization of preformed lytic granules to the effector-target contact zone [48]. Finally, NK cells initialize the release of their cargo of preformed lytic granules containing both PRF1 and GZMs at the immunological synapse, a process known as degranulation (Figure 1) [49,50,51]. PRF1 monomers are glycoproteins that, similarly to the complement membrane attack complex, aggregate and form a pore in the membrane of the tumor cell, hence allowing the internalization of GZMs into the cytosol and eliciting osmotic imbalance [50]. Additionally, direct endocytosis of GZMs by target cells has been proposed as an alternative method to GZM protease delivery [52,53,54]. Nevertheless, Prf1−/− mice demonstrated a complete abrogation of target cell death in a lytic granule-dependent manner, supporting the relevance of the pore formation over the direct endocytosis of GZMs [55,56]. Furthermore, PRF1 induces the formation of target cell membrane invaginations, allowing GZMs to be delivered by endocytosis [52].
PRF1 is essential for the NK cell control of tumor development and metastasis [57,58,59,60]. Indeed, PRF1-deficient mice developed B-cell lymphomas in 60% of cases [58]. Accordingly, patients with type 2 familial hemophagocytic lymphohistiocytosis with biallelic mutations affecting the PRF1 gene were observed to develop hematological malignancies in 50% of cases during childhood or adolescence, whereas NK cell dysfunction has been described [61,62].
GZMs are proteins from the family of serine proteases that are localized in granules, preventing the host cell from being damaged by its own cargo. To date, five different GZMs have been described in humans (A, B, H, K, and M). Granzymes A (GZMA) and B (GZMB) are the most abundant constituents of granules and have been deeply studied due to its important function in eliminating malignant or transforming cells. On the contrary, the role of GZMH, -K, and -M remains poorly understood [127,128,129].
GZMA induces cell death by a caspase-independent pathway. This serine protease alters the mitochondrial inner membrane potential, leading to the release of reactive oxygen species (ROS) and, in contrast to GZMB, does not affect pro-apoptotic proteins such as smac/DIABLO or cytochrome c [130]. ROS production prompts endoplasmic reticulum (ER)-associated SET complex translocation to the nucleus, where SET is cleaved by GZMA, releasing nucleases associated to DNA damage, such as NM23-H1 DNase that, along with TRX1, degrades DNA and leads to cell death [131,132,133]. This protease also targets histone H1, KU70, and DNA damage sensor poly(adenosine 5′-diphosphate-ribose) polymerase-1 (PARP), presumably facilitating DNase activity [134,135]. Likewise, GZMA has a trypsin-like activity, cleaving after asparagine (Asp) and lysine (Lys) residues, which generates single-stranded DNA nicks that cannot be detected in GZMB-related apoptosis [136].
GZMB is generally expressed by NK cells and cytotoxic T lymphocytes, although this protease may also be found in myeloid cells, such as macrophages, plasmacytoid dendritic cells, neutrophils, basophils, or mast cells [137,138,139,140]. This serine protease essentially cleaves after Asp residues, showing a wide variety of substrates. As an example, GZMB exerts a direct proteolytic processing of executioner procaspases (being its main targets caspase-3 and -7), hence eliciting caspase-dependent apoptosis [141]. GZMB also cleaves the BH3-only protein Bid, inducing the truncated form of this protein and leading to Bak/Bax activation and pore formation on the mitochondria outer membrane, followed by the release of pro-apoptotic proteins, such as smac/DIABLO, cytochrome c, high temperature requirement A2 (HtrA2)/Omi serine protease, apoptosis inducing factor (AIF), and endonuclease-G (Endo-G) [141].
Granzyme M (GZMM) is abundantly expressed on NK cells and has been classically related to innate immune responses. This granzyme promotes caspase- and mitochondria-independent cell death by direct cleavage of α-tubulin and actin-plasma membrane linker ezrin, targeting key components of the cytoskeleton [142,143]. To date, the role of GZMM in immunosurveillance and its antitumor activity have not been fully clarified. On the one hand, GZMM-deficient mice displayed normal NK cell development and cytotoxic capacity, suggesting that this granzyme does not play a crucial role on NK cell-mediated cytotoxicity [144]. Further, GZZM has been described to promote epithelial-to-mesenchymal-transition (EMT) in vitro [145]. On the other hand, the generation of GZMB−/− and GZMM−/− mice models unveiled that both granzymes are required for growth inhibition of a transplanted sarcoma cell line during adoptive NK cell transfer [146]. Further, GZMM has been demonstrated to effectively inactivate proteinase inhibitor 9, a GZMB inhibitor, suggesting that the former may indirectly play an antitumor role [147].
Although, as mentioned above, deficiencies in PRF1 correlate with diminished target cell lysis by effector T lymphocytes and NK cells and increased risk of cancer, the importance of lacking individual GZMs remains elusive [148,149]. Mice deficient in GZMA and GZMB have been reported to show an increased sensitivity to NK cell-mediated cytotoxicity [150,151]. Interestingly, GZMB expression has been reported in cancer cells from diverse solid tumors, such as breast cancer, head and neck cancer, and lung carcinoma, where it has been suggested to intervene in extracellular matrix remodeling, promoting EMT [151,152,153]. In line with this, GZMB expression has been suggested to promote tumor immunoevasion, favoring B regulatory (Breg) and T regulatory (Treg)-mediated immune suppression, dampening antitumor NK cell and T lymphocyte responses, albeit contradictory results that have been obtained to date [154,155,156,157,158].
Granulysin is delivered, along with GZMs, in a PRF1-dependent manner. Granulysin is a saposin-like antibacterial cytolytic protein expressed by NK cells and cytotoxic T lymphocytes. It is mainly involved in host defense against intracellular pathogens by altering the target cell membrane permeability. In the context of cancer, granulysin-mediated apoptosis may be caspase-dependent or independent [159]. Granulysin is able to activate plasma membrane sphingomyelinase, triggering sphingomyelin degradation and ceramide production, and stimulating pro-apoptotic pathways [160]. Likewise, this cytolytic protein may alter ER membrane permeability, increasing the intracellular levels of cytosolic Ca2+, ROS production, and inducing the loss of mitochondrial membrane potential [161,162]. Altogether, this intracellular cascade of events activates caspase-dependent apoptosis, via cytochrome c release among other pro-apoptotic factors [162,163,164]. However, little evidence of the role of granulysin in antitumor immunity are available, since in vivo activity has not been completely demonstrated. Increased granulysin expression has been correlated to good prognosis in a wide variety of cancers, including solid and hematological malignancies [165,166,167,168,169,170]. Therapeutic strategies based on granulysin analogues have been studied, showing in vitro activity in cell lines and primary chronic lymphocytic leukemia (CLL) and multiple myeloma (MM) cells [171]. However, scarce data about its potential in vivo are available to date and deserves further investigations [172,173].

3. Resistance to NK Cell-Mediated Cytotoxicity

3.1. Resistance to Apoptosis: Genetic Alterations Linked to Genes Governing Apoptosis

Tumor cells undergo a wide number of genetic and epigenetic alterations throughout cancer development that provide survival advantages, including the ability to evade apoptosis [15]. Concomitantly, malignant cells become more resistant to NK cell-mediated elimination, escaping immune surveillance and, hence, favoring tumor progression. Tumor-derived alterations conferring resistance to programmed cell death usually affect genes controlling apoptotic signaling pathways at different levels. A common mechanism to suppress apoptosis in tumor cells relies on the impairment of caspase function, frequently via genetic modifications. For instance, caspase-8 is highly mutated in human cancers [174]. An early screening study identified thirteen different mutations in the CASP8 gene, which altered protein activation, in an array of tumors from diverse origins, with a higher incidence of mutation in gastric cancer [63]. Further, a caspase-8-defective mutant characterized by a single amino acid deletion (Leu62del) was described in vulvar squamous carcinoma and a frameshift mutation (1225_1226delTG) is likely responsible for the loss of caspase-8 activity in hepatocellular carcinoma, suggesting that genetic alterations linked to caspase-8 inactivation might vary depending on the type of cancer [64,65]. A recent work regarding CASP6, a significantly mutated gene in colon and gastric cancer [66], found tumor-associated mutations that decrease the catalytic efficiency of the protein, thus contributing to the resistance of cancer cells to programmed cell death [175]. Likewise, analysis of CASP3 gene sequence revealed fourteen somatic mutations throughout a panel of tumor samples from different origins, alterations that might render this protein insensitive to GZMB-mediated cleavage and, thus, directly interfere with NK cell-mediated killing [67]. Several other studies also unveiled the presence of inactivating mutations in tumor cells that hinder the function of other caspases, such as caspase-4, -5, -7, and -9 [68,69,70,71].
Tumor cells may also become resistant to programmed cell death through the abnormal activity of molecules that suppress the apoptotic cascade. At this respect, the aberrant expression of survivin is achieved in advanced stages of neuroblastoma via chromosome 17q gain, as occurs with c-IAP1, a protein overexpressed in a wide variety of tumors due to gene amplification [72,73,74]. Alternatively, c-IAP2 shows enhanced activity as a consequence of chromosomal translocations. The gene rearrangement (t(11;18)) results in the fusion protein c-IAP2/MALT1, present in a large proportion of MALT (mucosa-associated lymphoid tissue) lymphomas [75]. This protein might confer resistance to apoptosis through interaction with regulators of the apoptotic program, such as smac/DIABLO or TRAF2 (TNF receptor-associated factor 2) [75,176,177].
Additionally, downregulation or suppression of pro-apoptotic proteins by tumor cells results in resistance to NK cell-mediated apoptosis. The large group of proteins that regulate the mitochondrial apoptotic response is subjected to genetic modulation as well. Frameshift mutations leading to inactivation of the pro-apoptotic protein Bax have extensively been described in colon and gastric cancers with microsatellite instability [76,77,78]. These tumors also harbor mutations in Apaf-1 in a low frequency, which might contribute to cancer progression via impairment of a correct assembly of the apoptosome. BAX gene mutations have also been identified in certain hematologic malignancies, such as CLL or Burkitt’s lymphoma [79,80,178]. In line with this, the BCL2 locus is subjected to chromosomal translocation (t(14;18)), a typical feature reported in diffuse large B-cell lymphoma (DLBCL) that translates into BCL2 overexpression [82]. Likewise, oncogenic viruses, such as human herpesvirus 8 (HHV8), encode homologue proteins to BCL2 and FLICE (FADD-like IL-1β-converting enzyme)-inhibitory protein (c-FLIP), therefore protecting cancer cells from apoptosis [83,84]. Other members of the BCL2 family of proteins also carry tumor-associated alterations that tip the intracellular balance towards an anti-apoptotic state, e.g., Bim deletion in mantle cell lymphoma (MCL) or Noxa mutations in DLBCL [88,89]. Overexpression of BCL2 family members has also been associated with ADCC-based therapy resistance [179,180].
In general, the alterations described herein ultimately result in attenuation or loss of the apoptotic potential of tumor cells, a key stage in NK cell-mediated elimination. Hence, cancer-associated alterations that lead to functionally defective apoptosis not only provide survival advantages in terms of tumor development and progression, but also evade the immune surveillance carried out by NK cells and other cytotoxic immune subsets. The particular features of tumor cells that provide protection against PRF1/GZMs and death receptor-mediated NK cell cytotoxicity will be discussed next.

3.2. Resistance to Death Receptors-Mediated Cell Death

As previously described, the activation of the extrinsic apoptotic cascade relies on the engagement of death receptors that transduce the death signal to intracellular components of the pathway. Consequently, inactivation of such receptors results in the dysregulation of apoptosis, a strategy linked to tumor progression. A total of seven mutations in TRAIL receptors (three in TRAIL-R1 and four in TRAIL-R2) were detected in metastatic breast cancer samples and the expression of each mutant variant translated into defective apoptosis in HEK293 cells [93]. Somatic mutations in TRAIL receptor genes have also been described in various human tumors, although their frequency is relatively low [90,91,95,96]. Four of the tumor-associated mutations identified so far (L334F, E326K, E338K, and K386N) caused loss of TRAIL-R2 function via defective recruitment of intracellular components, including caspase-8 or FADD [181]. Further, the loss of chromosome 8p correlated with downregulation of TRAIL-R1 and TRAIL-R2 and, concomitantly, resistance to TRAIL-induced apoptosis in an array of B-cell malignancies [92]. This allelic deletion is typically present in epithelial carcinomas as well and is associated with poor prognosis and metastasis [93,182,183,184,185]. Following the same line, FAS gene exhibits loss-of-function mutations in tumor cells that avoid apoptosis activation upon CD95L/FasL engagement [97].
As mentioned above, NK cells eliminate target cells by the activation of death receptors and release of cytotoxic granules containing PRF1, GZMs, and granulysin. Nevertheless, both mechanisms rely on the tumor cell apoptotic machinery. Indeed, the alteration of apoptosis mediators are present in all types of tumors, representing a critical hallmark of cancer [15].
The DISC complex function upon receptor-ligand binding is tightly regulated by c-FLIP, a homologue of caspase-8 that lacks caspase activity and binds to FADD and caspase-8 or -10, thereby inhibiting the DISC complex formation. High expression of c-FLIP, countervailing TRAIL-mediated apoptosis, has been correlated with apoptosis resistance and poor prognosis in a wide variety of solid tumors and hematological malignancies [85,86,87,186,187]. Further, c-FLIP overexpression is related to extrinsic apoptosis, but not to GZM/PRF1 pathway resistance, whereas its role in chemotherapy-mediated apoptosis resilience remains elusive [188,189,190,191]. In vivo, c-FLIP overexpression protected tumor cells from lysis by NK cells in a PRF1-deficient murine model, once again highlighting the importance of this protein in cancer [192]. As a result of alternative splicing, three different c-FLIP variants are expressed: c-FLIP-long (c-FLIPL), c-FLIP-short (c-FLIPS), and c-FLIP-Raji (c-FLIPR). All three variants conserve the death effector domain (DED) that binds to the DISC complex, hence inhibiting apoptosis [193,194]. Furthermore, c-FLIPL acts as an anti-apoptotic protein depending on its expression level; high levels of c-FLIPL compete with caspase-8 showing anti-apoptotic features, whereas low levels of c-FLIPL enhance procaspase-8 processing, thus favoring apoptosis [195].
Overexpression of decoy receptors stands as a resistance mechanism linked to death receptors, since it has been correlated to poor prognosis and lack of response to FasL and TRAIL. Decoy receptor 3 (DcR3) is a protein related to FasL and LIGHT (TNFSF14) suppression, whose aberrant expression has been detected in several tumors and might play a role in triggering EMT [100,101,102,196,197]. Consistently, TRAIL-R3 and TRAIL-R4 altered expression has been described in several tumors, including breast, prostate, and pancreatic cancers [103,104,105,198,199]. Likewise, the anti-apoptotic activity of decoy receptors not only relies on receptor-ligand competition; TRAIL-R4 activates and sustains NF-κB signaling, thus promoting leukemic cell survival [200,201]. In line with this, the expression of soluble receptors that behave as a decoy for death ligands represents another resistance mechanism associated with the extrinsic apoptotic pathway [98,99]. Besides the pro-apoptotic and anti-tumor functions of death receptors, tumor-promoting functions have also been described for Fas/FasL. Growing evidence, such as Fas expression on cancer cells, suggest that this protein also harbors non-apoptotic activity. Furthermore, elimination of Fas/FasL in mouse models of ovarian and liver cancers resulted in reduced tumor incidence and growth, probably due to the death induced by Fas/FasL elimination (DICE) phenomenon [202]. Further, triggering DICE in cancer cells by targeting the Fas/FasL axis might represent a therapeutic option in the near future [203,204].
Although in vitro/in vivo and preclinical TRAIL-based therapies demonstrated encouraging results and low toxicity owing to tumor-specific activity, the use of death receptors, such as FasL or TNF, as anticancer therapy was soon dampened [205,206,207,208,209,210]. Different approaches to TRAIL-based therapies have been suggested, including recombinant TRAIL and agonistic monoclonal antibodies (mAbs), targeting TRAIL-R1 and/or TRAIL-R2. Despite that fact that TRAIL-based therapies were generally well tolerated, phase I/II clinical trials for a wide variety of cancers resulted in poor responses for the vast majority of patients [211,212,213,214,215,216]. Withal, different resistance mechanisms seem to limit the success of TRAIL-based therapies: (i) low persistence of recombinant TRAIL, (ii) whereas agonistics antibodies are receptor specific, recombinant TRAIL also binds to decoy receptors, (iii) depending on the tumor, TRAIL receptor apoptotic signaling preferably relies on TRAIL-R1 or TRAIL-R2, so agonistic mAbs to specific receptors must be carefully chosen [217,218,219,220], (iv) agonistic mAbs are weak apoptosis-inducers due the lack of death receptor homotrimers (reviewed in [21] and [221]) and, (v) in some cases, severe hepatotoxicity was detected [222,223,224,225]. Due to the lack of success of recombinant TRAIL and agonistic mAbs as monotherapy, combinatorial therapies along with CDK9 inhibitors or SMAC mimetics among others have currently been studied [226,227,228,229,230].

3.3. Resistance to Perforin, Granzymes and Granulysin-Mediated Cell Death

Tumor cells have evolved distinct strategies to interfere with PRF1 and/or GZM function, thus leading to immune escape. Such NK cell shaping may be achieved via direct mechanisms, such as release of soluble factors by cancer cells or through recruitment of suppressor cells that indirectly hinder NK cell antitumor activity. Since ADCC-mediated cytotoxicity is PRF1 and GZM-dependent, resistance mechanisms targeting these immune mediators limit the efficacy of ADCC-based therapies [231,232]. Further, loss of targeted antigens or antibody endocytic uptake also correlate with faulty ADCC [233].
Given the largely proven vital role of PRF1 in NK cell-mediated tumor rejection, this protein arises as a highly-targeted component of the degranulation pathway [57,58,59]. A typical strategy reported in a wide variety of tumors entails the inhibition or downregulation of PRF1 expression on NK cells [106,107,108,124,234]. In line with this, coculture experiments unveiled that myeloid-derived suppressor cells (MDSCs) from mammary adenocarcinoma-bearing mice reduced PRF1 levels in NK cells, correlating with decreased NK cell cytotoxicity in vivo [109]. Cancer-associated fibroblasts (CAFs) also display a suppressive activity that partially relies on PRF1 downmodulation in NK cells [110,111,112]. This mechanism of NK cell evasion not only affects PRF1 expression; several studies have reported lower levels of GZMB, as well as, CD107a in tumor-infiltrating NK cells, an altered phenotype that translates into an attenuated antitumor immune response [107,108,115,124,235]. Apart from this extended evasion strategy, an early study involving acute myeloid leukemia (AML) samples revealed that the intrinsic apoptosis resistance associated with this type of cancer relies on an impaired binding of PRF1 to the surface of the tumor cells [113]. Similarly, TGF-β-producing tumors are more likely to resist NK cell-mediated cytotoxicity, since PRF1 mobilization to the immune synapse was abrogated in NK cells cocultured with Burkitt’s lymphoma Raji cells in the presence of this immunosuppressive cytokine [114]. A recent study in breast cancer cell lines discovered a substantial accumulation of F-actin near the immune synapse in tumor cells upon encountering NK cells [125]. Inhibition of this actin response led to an increase in NK cell-mediated apoptosis of tumor cells, hence bringing to light a novel mechanism of immune escape. The stability of the immune synapse is crucial for an efficient cytolytic killing of tumor cells upon NK cell recognition. Hypoxic conditions, through activation of the transcription factor HIF-1α, triggered selective degradation of connexin-43, a major component of gap junctions in melanoma cells, which correlated with decreased susceptibility to NK cell cytotoxicity due to immune synapse destabilization [126]. The adverse tumor microenvironment may therefore interfere with the degranulation process, actively contributing to tumor resistance to NK cell-mediated apoptosis, which will be further discussed in this work. Accordingly, GZMB degradation was boosted by activation of autophagy in hypoxic human breast cancer cells [116,117]. Inhibition of autophagy by targeting beclin1, a key regulator of autophagosome formation, restored the killing capacity of NK cells in vivo, together with the presence of GZMB in hypoxic tumor cells in vitro. Serine protease inhibitors, best known as serpins, stand out as a major culprit of resistance to apoptosis in tumor cells, since they are suppressors of different members of the GZM family. Serpin B9 (protease inhibitor 9; PI-9) specifically targets the proteolytic activity of GZMB and diverse studies have reported increased intracellular expression of this serpin in a broad subset of human cancers [118,119,120,236,237]. Serpin B9-expressing tumor cell lines proved to be more resistant to GZMB-induced apoptosis, implying that this evasion strategy might weaken the tumoricidal potential of NK cells via blockade of the degranulation pathway [237]. Along this line, in vitro experiments revealed serpin B4 (squamous cell carcinoma antigen 2; SCCA-2) as an inhibitor of GZMM-mediated cell death, which is highly expressed by squamous cell carcinomas [121,122,123,238]. NK cell-induced apoptosis was reduced upon overexpression of serpin B4 in HeLa cells, further reinforcing the role of serpins in reducing tumor elimination by the immune system.
No direct impairment of granulysin function has been described in cancer so far. An early report established a link between lower expression of granulysin on NK cells and cancer progression in patients with disparate types of cancer [168]. Additionally, this decreased granulysin expression correlated with reduced numbers of circulating NK cells, which might further contribute to tumorigenesis. A set of mechanisms acquired by tumor cells that negatively target granulysin expression, hence attenuating the antitumor potential of NK cells, might explain these observations. Nonetheless, the relevance of defective or decreased granulysin levels in tumor evasion to immune elimination merits future investigation.
Altogether, these data bring to light the importance of the PRF1/GZM pathway in cancer immunosurveillance, since tumor cells have developed a myriad of mechanisms to interfere with this process, acquiring resistance to NK cell-mediated apoptosis. Restoring this degranulation capacity might prove a useful immunotherapeutic approach to achieve tumor rejection in patients with cancer.

3.4. Resistance to Apoptosis: Influence of the Tumor Microenvironment

The diverse components—from tumor-associated immune cells to stromal cells or even soluble factors—of the tumor microenvironment (TME) take an active part in cancer establishment and progression at different levels. Tumor cells exploit the adverse conditions of the TME for their own benefit, for instance, by avoiding NK cell-mediated recognition and cytotoxicity or favoring immunosuppression.
The TME typically displays chronic stress conditions, such as hypoxia or oxidative stress, that can negatively affect NK cell antitumor function both in a direct manner or via other cell subsets [5]. At this respect, the presence of ROS in the TME frequently translates into NK cell dysfunction [239,240]. In vitro studies reported a decrease in NKG2D and NKp46 levels in CD56dim NK cells elicited by phagocyte-derived ROS, which might account for the oxidative stress-associated attenuation of NK cell cytotoxicity [241]. Likewise, hypoxia led to downregulation of activating receptors on NK cells in vitro, which correlated with reduced tumor sensitivity to NK cell-mediated elimination [242]. The detrimental effect of hypoxia on NK cells has also been described in in vivo settings, reinforcing the role of stress conditions in tumor evasion of NK cell responses [243,244].
Upon exposure to hypoxic stress, tumor cells recruit immunosuppressive cells to the TME via chemotactic factors. As an illustration, MDSCs arrive to the tumor niche following the trail of tumor-derived CCL26 (C–C motif chemokine ligand 26) in hepatocellular carcinoma [245]. MDSCs, as already mentioned, suppress NK cell function in the TME by inhibiting perforin production, among other mechanisms [109]. Treg cells and tumor-associated macrophages (TAMs) infiltrate the TME, where, together with MDSCs, they release immunosuppressive cytokines, mainly TGF-β, which is largely known to hamper NK cell-mediated tumor killing, including ADCC, by decreasing GZMB and FasL expression in NK cells [14,246,247,248,249,250,251,252]. Further, ROS production by these subsets strengthens the oxidative status of the TME, hence deepening NK cell suppression [239,253].
Additionally, tumor cells undergo distinct adaptations to overcome the challenging conditions of the TME, some of which confer apoptotic resistance. Hypoxia modulates the balance of crucial proteins governing apoptosis, tipping the scale towards an anti-apoptotic cellular state. Hypoxic tumor cells display reduced levels of pro-apoptotic members of the BCL2 family, such as Bax [254,255]. Conversely, several anti-apoptotic proteins are increased in hypoxic tumor cells, including c-IAP2 and Mcl-1 [256,257]. Similarly, ROS-dependent stimulation of Akt might lead to apoptosis evasion through inactivation of caspase-9 and Bad [258,259]. These survival advantages acquired by tumor cells under stress situations not only support cancer progression, but also protect malignant cells from NK cell-mediated cell death.
Interestingly, non-immune cells from the tumor site contribute to cancer resistance to NK cell-mediated apoptosis. The tumor-associated stroma is predominantly represented by CAFs in the majority of cancers [260]. These stromal cells shape the TME and are also strongly influenced by other elements present in the tumor site. Recent studies brought to light an inhibitory effect of colon carcinoma-isolated CAFs on NK cell activity, which partly relied on the downregulation of NKG2D and NKp44 as well as perforin and GZMB expression [112,261]. In a similar manner, melanoma-associated fibroblasts exhibited increased secretion of matrix metalloproteinases (MMPs) that, in turn, release soluble MICA and MICB from tumor cells, reducing the surface levels of these NK cell activating ligands and favoring NK cell exhaustion [8,262]. CAFs also secrete a whole array of immunosuppressive cytokines that limit immune responses, such as IL-6, IL-10, and TGF-β [263,264,265]. Among these molecules, prostaglandin E2 (PGE2) and indoleamine 2,3-dioxygenase (IDO) stand out as central regulators of NK cell function. NK cell killing of tumor cells was compromised as a result of PGE2 and/or IDO production by CAFs in several types of cancer like melanoma, hepatocellular carcinoma, and thyroid cancer [110,111,266,267]. Mesenchymal stem cells, another stromal cell population, have also been described to attenuate NK cell tumor elimination via PGE2 and IDO secretion to the TME, further supporting the role of the tumor stroma in the evasion of cancer surveillance exerted by NK cells [268,269].
The harsh conditions of the TME together with the cellular components of the tumor niche deeply contribute to creating an immunosuppressive environment that restricts NK cell activity, promoting tumor progression and resistance to apoptotic cell death.

4. Concluding Remarks

The antitumor function of the immune system strongly relies in the induction of apoptotic malignant cell death by certain cytotoxic lymphocytes. Among these populations, NK cells stand out as cells with a superior tumor cell killing activity via exocytosis of granules bearing pro-apoptotic mediators or activation of the death receptor pathway. However, malignant cells often subvert NK cell function by manifold mechanisms, which we outlined in the review herein. Most (if not all) anticancer chemotherapies are linked to tumor cell demise brought about by induction of, mostly, mitochondrial pathway-dependent programmed cell death. While malignant cell resilience to conventional therapeutic interventions is frequently observed, the immune surveillance of tumors operates as an extrinsic control mechanism; alerted upon cancer cell overexpression of stress-regulated self-molecules, NK cells trigger target cell death via promotion of apoptosis. Consequently, malignant cells endowed with mechanisms that circumvent apoptosis might be resilient to both certain therapies and the cytotoxic response elicited by NK cells. Hence, a great deal of effort needs to be put in order to unveil hitherto unknown cell intrinsic and extrinsic mechanisms that render tumor cells resistant to therapeutic and immune-dependent induction of apoptosis. In this sense, several combination therapies employing targeted agents and immunostimulatory mediators, which are currently under clinical evaluation, are promising regimens to overcome cancer cell resilience, limiting malignant progression by inducing apoptosis in, otherwise resistant, cancer cells.

Author Contributions

All the authors participated in the preparation, writing and revision of the manuscript. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by the Spanish grant of Instituto de Salud Carlos III (PI19/01353) and FEDER European Union. The funders had no role in the study design, data collection, or analysis, the decision to publish, or the preparation of the manuscript.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Chiossone, L.; Dumas, P.-Y.; Vienne, M.; Vivier, E. Natural killer cells and other innate lymphoid cells in cancer. Nat. Rev. Immunol. 2018, 18, 671–688. [Google Scholar] [CrossRef] [PubMed]
  2. López-Soto, A.; Gonzalez, S.; Smyth, M.J.; Galluzzi, L. Control of Metastasis by NK Cells. Cancer Cell 2017, 32, 135–154. [Google Scholar] [CrossRef] [PubMed]
  3. Lorenzo-Herrero, S.; López-Soto, A.; Sordo-Bahamonde, C.; Gonzalez, A.P.; Vitale, M.; Gonzalez, S. NK Cell-Based Immunotherapy in Cancer Metastasis. Cancers 2018, 11, 29. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  4. Sun, J.C.; Lanier, L.L. NK cell development, homeostasis and function: Parallels with CD8⁺ T cells. Nat. Rev. Immunol. 2011, 11, 645–657. [Google Scholar] [CrossRef] [PubMed]
  5. Lorenzo-Herrero, S.; Sordo-Bahamonde, C.; González, S.; López-Soto, A. Immunosurveillance of cancer cell stress. Cell Stress 2019, 3, 295–309. [Google Scholar] [CrossRef]
  6. Sivori, S.; Vacca, P.; Del Zotto, G.; Munari, E.; Mingari, M.C.; Moretta, L. Human NK cells: Surface receptors, inhibitory checkpoints, and translational applications. Cell. Mol. Immunol. 2019, 16, 430–441. [Google Scholar] [CrossRef]
  7. Villa-Álvarez, M.; Sordo-Bahamonde, C.; Lorenzo-Herrero, S.; Gonzalez-Rodriguez, A.P.; Payer, A.R.; Gonzalez-Garcia, E.; Villa-Álvarez, M.C.; López-Soto, A.; Gonzalez, S. Ig-Like Transcript 2 (ILT2) Blockade and Lenalidomide Restore NK Cell Function in Chronic Lymphocytic Leukemia. Front. Immunol. 2018, 9. [Google Scholar] [CrossRef]
  8. López-Soto, A.; Huergo-Zapico, L.; Acebes-Huerta, A.; Villa-Alvarez, M.; González, S. NKG2D signaling in cancer immunosurveillance. Int. J. Cancer 2014, 136, 1741–1750. [Google Scholar] [CrossRef]
  9. Topham, N.J.; Hewitt, E. Natural killer cell cytotoxicity: How do they pull the trigger? Immunol. 2009, 128, 7–15. [Google Scholar] [CrossRef]
  10. Gutiérrez-Cívicos, R.; Hurtado, A.M.; Torres-Moreno, D.; Sanchez-Blanco, J.J.; Español, I.; Consuegra-Sanchez, L.; Pérez-Ceballos, E.; Gutiérrez-Meca, M.D.; Jerez, A.; Conesa-Zamora, P. A polymorphism in FASL is associated with rituximab response in follicular lymphoma patients. Am. J. Hematol. 2016, 91, E305–E307. [Google Scholar] [CrossRef] [Green Version]
  11. Vega, M.I.; Huerta-Yepez, S.; Jazirehi, A.R.; Garban, H.; Bonavida, B. Rituximab (chimeric anti-CD20) sensitizes B-NHL cell lines to Fas-induced apoptosis. Oncogene 2005, 24, 8114–8127. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  12. Seyfizadeh, N.; Seyfizadeh, N.; Hasenkamp, J.; Huerta-Yepez, S.; Information, P.E.K.F.C. A molecular perspective on rituximab: A monoclonal antibody for B cell non Hodgkin lymphoma and other affections. Crit. Rev. Oncol. 2016, 97, 275–290. [Google Scholar] [CrossRef] [PubMed]
  13. Stel, A.J.; Cate, B.T.; Jacobs, S.; Kok, J.W.; Spierings, D.C.; Dondorff, M.; Helfrich, W.; Kluin-Nelemans, H.C.; De Leij, L.F.M.H.; Withoff, S.; et al. Fas receptor clustering and involvement of the death receptor pathway in rituximab-mediated apoptosis with concomitant sensitization of lymphoma B cells to fas-induced apoptosis. J. Immunol. 2007, 178, 2287–2295. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  14. Bedi, A.; Chang, X.; Noonan, K.; Pham, V.; Bedi, R.; Fertig, E.J.; Considine, M.; Califano, J.A.; Borrello, I.; Chung, C.H.; et al. Inhibition of TGF-β enhances the in vivo antitumor efficacy of EGF receptor-targeted therapy. Mol. Cancer Ther. 2012, 11, 2429–2439. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  15. Hanahan, D.; A Weinberg, R. Hallmarks of Cancer: The Next Generation. Cell 2011, 144, 646–674. [Google Scholar] [CrossRef] [Green Version]
  16. Lowe, S.W.; Cepero, E.; Evan, G. Intrinsic tumour suppression. Nature 2004, 432, 307–315. [Google Scholar] [CrossRef]
  17. Peter, M.E.; Hadji, A.; E Murmann, A.; Brockway, S.; Putzbach, W.; Pattanayak, A.; Ceppi, P. The role of CD95 and CD95 ligand in cancer. Cell Death Differ. 2015, 22, 549–559. [Google Scholar] [CrossRef]
  18. Yamada, A.; Arakaki, R.; Saito, M.; Kudo, Y.; Ishimaru, N. Dual Role of Fas/FasL-Mediated Signal in Peripheral Immune Tolerance. Front. Immunol. 2017, 8, 1449. [Google Scholar] [CrossRef] [Green Version]
  19. Kaufmann, S.; Steensma, D.P. On the TRAIL of a new therapy for leukemia. Leukemia 2005, 19, 2195–2202. [Google Scholar] [CrossRef] [Green Version]
  20. Mirandola, P.; Ponti, C.; Gobbi, G.; Sponzilli, I.; Vaccarezza, M.; Cocco, L.; Zauli, G.; Secchiero, P.; Manzoli, F.A.; Vitale, M. Activated human NK and CD8+ T cells express both TNF-related apoptosis-inducing ligand (TRAIL) and TRAIL receptors but are resistant to TRAIL-mediated cytotoxicity. Blood 2004, 104, 2418–2424. [Google Scholar] [CrossRef]
  21. Von Karstedt, S.; Montinaro, A.; Walczak, H. Exploring the TRAILs less travelled: TRAIL in cancer biology and therapy. Nat. Rev. Cancer 2017, 17, 352–366. [Google Scholar] [CrossRef] [PubMed]
  22. Sprick, M.R.; A Weigand, M.; Rieser, E.; Rauch, C.T.; Juo, P.; Blenis, J.; Krammer, P.H.; Walczak, H. FADD/MORT1 and Caspase-8 Are Recruited to TRAIL Receptors 1 and 2 and Are Essential for Apoptosis Mediated by TRAIL Receptor 2. Immunity 2000, 12, 599–609. [Google Scholar] [CrossRef] [Green Version]
  23. Pitti, R.M.; Marsters, S.A.; Lawrence, D.A.; Roy, M.; Kischkel, F.C.; Dowd, P.; Huang, A.; Donahue, C.J.; Sherwood, S.W.; Baldwin, D.T.; et al. Genomic amplification of a decoy receptor for Fas ligand in lung and colon cancer. Nature 1998, 396, 699–703. [Google Scholar] [CrossRef] [PubMed]
  24. Neumann, S.; Hasenauer, J.; Pollak, N.; Scheurich, P. Dominant Negative Effects of Tumor Necrosis Factor (TNF)-related Apoptosis-inducing Ligand (TRAIL) Receptor 4 on TRAIL Receptor 1 Signaling by Formation of Heteromeric Complexes. J. Boil. Chem. 2014, 289, 16576–16587. [Google Scholar] [CrossRef] [Green Version]
  25. Merino, D.; Lalaoui, N.; Morizot, A.; Schneider, P.; Solary, E.; Micheau, O. Differential Inhibition of TRAIL-Mediated DR5-DISC Formation by Decoy Receptors 1 and 2. Mol. Cell. Boil. 2006, 26, 7046–7055. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  26. Sheridan, J.P.; Marsters, S.A.; Pitti, R.M.; Gurney, A.; Skubatch, M.; Baldwin, D.; Ramakrishnan, L.; Gray, C.L.; Baker, K.; Wood, W.I.; et al. Control of TRAIL-Induced Apoptosis by a Family of Signaling and Decoy Receptors. Science 1997, 277, 818–821. [Google Scholar] [CrossRef]
  27. Sanlioglu, A.D.; Dirice, E.; Aydin, C.; Erin, N.; Koksoy, S.; Sanlioglu, S. Surface TRAIL decoy receptor-4 expression is correlated with TRAIL resistance in MCF7 breast cancer cells. BMC Cancer 2005, 5, 54. [Google Scholar] [CrossRef] [Green Version]
  28. Leblanc, H.N.; Ashkenazi, A. Apo2L/TRAIL and its death and decoy receptors. Cell Death Differ. 2003, 10, 66–75. [Google Scholar] [CrossRef] [Green Version]
  29. Kischkel, F.C.; Hellbardt, S.; Behrmann, I.; Germer, M.; Pawlita, M.; Krammer, P.H.; Peter, M.E. Cytotoxicity-dependent APO-1 (Fas/CD95)-associated proteins form a death-inducing signaling complex (DISC) with the receptor. EMBO J. 1995, 14, 5579–5588. [Google Scholar] [CrossRef]
  30. Schug, Z.T.; Gonzalvez, F.; Houtkooper, R.H.; Vaz, F.M.; Gottlieb, E. BID is cleaved by caspase-8 within a native complex on the mitochondrial membrane. Cell Death Differ. 2010, 18, 538–548. [Google Scholar] [CrossRef]
  31. Korsmeyer, S.J.; Wei, M.C.; Saito, M.; Weiler, S.; Oh, K.J.; Schlesinger, P.H. Pro-apoptotic cascade activates BID, which oligomerizes BAK or BAX into pores that result in the release of cytochrome c. Cell Death Differ. 2000, 7, 1166–1173. [Google Scholar] [CrossRef] [PubMed]
  32. Tanaka, M.; Itai, T.; Adachi, M.; Nagata, S. Downregulation of Fas ligand by shedding. Nat. Med. 1998, 4, 31–36. [Google Scholar] [CrossRef] [PubMed]
  33. Reilly, L.A.O.; Tai, L.; Lee, L.; Kruse, E.A.; Grabow, S.; Fairlie, W.; Haynes, N.M.; Tarlinton, D.; Zhang, J.-G.; Belz, G.; et al. Membrane-bound Fas ligand only is essential for Fas-induced apoptosis. Nature 2009, 461, 659–663. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  34. Schneider, P.; Holler, N.; Bodmer, J.-L.; Hahne, M.; Frei, K.; Fontana, A.; Tschopp, J. Conversion of Membrane-bound Fas(CD95) Ligand to Its Soluble Form Is Associated with Downregulation of Its Proapoptotic Activity and Loss of Liver Toxicity. J. Exp. Med. 1998, 187, 1205–1213. [Google Scholar] [CrossRef]
  35. Wajant, H.; Moosmayer, D.; Wüest, T.; Bartke, T.; Gerlach, E.; Schönherr, U.; Peters, N.; Scheurich, P.; Pfizenmaier, K. Differential activation of TRAIL-R1 and -2 by soluble and membrane TRAIL allows selective surface antigen-directed activation of TRAIL-R2 by a soluble TRAIL derivative. Oncogene 2001, 20, 4101–4106. [Google Scholar] [CrossRef] [Green Version]
  36. Maecker, H.L.; Yun, Z.; Maecker, H.T.; Giaccia, A.J. Epigenetic changes in tumor Fas levels determine immune escape and response to therapy. Cancer Cell 2002, 2, 139–148. [Google Scholar] [CrossRef] [Green Version]
  37. Price, S.; Shaw, P.A.; Seitz, A.; Joshi, G.; Davis, J.; Niemela, J.E.; Perkins, K.; Hornung, R.L.; Folio, L.; Rosenberg, P.S.; et al. Natural history of autoimmune lymphoproliferative syndrome associated with FAS gene mutations. Blood 2014, 123, 1989–1999. [Google Scholar] [CrossRef]
  38. Zörnig, M.; Grzeschiczek, A.; Kowalski, M.B.; Hartmann, K.U.; Möröy, T. Loss of Fas/Apo-1 receptor accelerates lymphomagenesis in E mu L-MYC transgenic mice but not in animals infected with MoMuLV. Oncogene 1995, 10, 2397–2401. [Google Scholar]
  39. Davidson, W.F.; Giese, T.; Fredrickson, T.N. Spontaneous Development of Plasmacytoid Tumors in Mice with Defective Fas–Fas Ligand Interactions. J. Exp. Med. 1998, 187, 1825–1838. [Google Scholar] [CrossRef]
  40. Adachi, M.; Suematsu, S.; Suda, T.; Watanabe, D.; Fukuyama, H.; Ogasawara, J.; Tanaka, T.; Yoshida, N.; Nagata, S. Enhanced and accelerated lymphoproliferation in Fas-null mice. Proc. Natl. Acad. Sci. USA 1996, 93, 2131–2136. [Google Scholar] [CrossRef] [Green Version]
  41. Fingleton, B.; Carter, K.J.; Matrisian, L.M. Loss of Functional Fas Ligand Enhances Intestinal Tumorigenesis in the Min Mouse Model. Cancer Res. 2007, 67, 4800–4806. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  42. Sedger, L.; Glaccum, M.B.; Schuh, J.C.L.; Kanaly, S.T.; Williamson, E.; Kayagaki, N.; Yun, T.; Smolak, P.; Le, T.; Goodwin, R.; et al. Characterization of the in vivo function of TNF-α-related apoptosis-inducing ligand, TRAIL/Apo2L, using TRAIL/Apo2L gene-deficient mice. Eur. J. Immunol. 2002, 32, 2246. [Google Scholar] [CrossRef]
  43. Cretney, E.; Takeda, K.; Yagita, H.; Glaccum, M.; Peschon, J.J.; Smyth, M.J. Increased susceptibility to tumor initiation and metastasis in TNF-related apoptosis-inducing ligand-deficient mice. J. Immunol. 2002, 168, 1356–1361. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  44. Diao, Z.; Shi, J.; Zhu, J.; Yuan, H.; Ru, Q.; Liu, S.; Liu, Y.; Zheng, D. TRAIL suppresses tumor growth in mice by inducing tumor-infiltrating CD4+CD25+ Treg apoptosis. Cancer Immunol. Immunother. 2012, 62, 653–663. [Google Scholar] [CrossRef] [PubMed]
  45. Finnberg, N.; Klein-Szanto, A.J.; El-Deiry, W. TRAIL-R deficiency in mice promotes susceptibility to chronic inflammation and tumorigenesis. J. Clin. Investig. 2007, 118, 111–123. [Google Scholar] [CrossRef]
  46. Grosse-Wilde, A.; Voloshanenko, O.; Bailey, S.L.; Longton, G.M.; Schaefer, U.; Csernok, A.I.; Schutz, G.; Greiner, E.F.; Kemp, C.J.; Walczak, H. TRAIL-R deficiency in mice enhances lymph node metastasis without affecting primary tumor development. J. Clin. Investig. 2007, 118, 100–110. [Google Scholar] [CrossRef] [Green Version]
  47. Grosse-Wilde, A.; Kemp, C.J. Metastasis suppressor function of tumor necrosis factor-related apoptosis-inducing ligand-R in mice: Implications for TRAIL-based therapy in humans? Cancer Res. 2008, 68, 6035–6037. [Google Scholar] [CrossRef] [Green Version]
  48. Martinez-Lostao, L.; Anel, A.; Pardo, J. How Do Cytotoxic Lymphocytes Kill Cancer Cells? Clin. Cancer Res. 2015, 21, 5047–5056. [Google Scholar] [CrossRef] [Green Version]
  49. Ewen, C.L.; Kane, K.P.; Bleackley, R.C. A quarter century of granzymes. Cell Death Differ. 2011, 19, 28–35. [Google Scholar] [CrossRef] [Green Version]
  50. Voskoboinik, I.; Smyth, M.J.; Trapani, J.A. Perforin-mediated target-cell death and immune homeostasis. Nat. Rev. Immunol. 2006, 6, 940–952. [Google Scholar] [CrossRef]
  51. Basile, G.D.S.; Ménasché, G.; Fischer, A. Molecular mechanisms of biogenesis and exocytosis of cytotoxic granules. Nat. Rev. Immunol. 2010, 10, 568–579. [Google Scholar] [CrossRef] [PubMed]
  52. Praper, T.; Sonnen, A.F.-P.; Kladnik, A.; Andrighetti, A.O.; Viero, G.; Morris, K.J.; Volpi, E.; Lunelli, L.; Serra, M.D.; Froelich, C.J.; et al. Perforin activity at membranes leads to invaginations and vesicle formation. Proc. Natl. Acad. Sci. USA 2011, 108, 21016–21021. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  53. Trapani, J.A.; Sutton, V.R.; Thia, K.Y.; Li, Y.Q.; Froelich, C.J.; Jans, D.A.; Sandrin, M.S.; Browne, K.A. A clathrin/dynamin- and mannose-6-phosphate receptor–independent pathway for granzyme B–induced cell death. J. Cell Boil. 2003, 160, 223–233. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  54. Veugelers, K.; Motyka, B.; Frantz, C.; Shostak, I.; Sawchuk, T.; Bleackley, R.C. The granzyme B–serglycin complex from cytotoxic granules requires dynamin for endocytosis. Blood 2004, 103, 3845–3853. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  55. Bolitho, P.; Voskoboinik, I.; Trapani, J.; Smyth, M.J.; Trapani, J.A. Apoptosis induced by the lymphocyte effector molecule perforin. Curr. Opin. Immunol. 2007, 19, 339–347. [Google Scholar] [CrossRef] [PubMed]
  56. Shi, L.; Keefe, D.; Durand, E.; Feng, H.; Zhang, N.; Lieberman, J. Granzyme B binds to target cells mostly by charge and must be added at the same time as perforin to trigger apoptosis. J. Immunol. 2005, 174, 5456–5461. [Google Scholar] [CrossRef] [Green Version]
  57. Kägi, D.; Ledermann, B.; Bürki, K.; Seiler, P.; Odermatt, B.; Olsen, K.J.; Podack, E.R.; Zinkernagel, R.M.; Hengartner, H.; K, B.L.D. Cytotoxicity mediated by T cells and natural killer cells is greatly impaired in perforin-deficient mice. Nature 1994, 369, 31–37. [Google Scholar] [CrossRef]
  58. Smyth, M.J.; Thia, K.Y.; Street, S.E.; MacGregor, D.; Godfrey, D.; Trapani, J.A. Perforin-Mediated Cytotoxicity Is Critical for Surveillance of Spontaneous Lymphoma. J. Exp. Med. 2000, 192, 755–760. [Google Scholar] [CrossRef] [Green Version]
  59. Broek, M.E.V.D.; Kägi, D.; Ossendorp, F.; Toes, R.; Vamvakas, S.; Lutz, W.K.; Melief, C.J.; Zinkernagel, R.M.; Hengartner, H. Decreased tumor surveillance in perforin-deficient mice. J. Exp. Med. 1996, 184, 1781–1790. [Google Scholar] [CrossRef] [Green Version]
  60. Smyth, M.J.; Thia, K.Y.; Cretney, E.; Kelly, J.M.; Snook, M.B.; A Forbes, C.; A Scalzo, A. Perforin is a major contributor to NK cell control of tumor metastasis. J. Immunol. 1999, 162, 6658–6662. [Google Scholar]
  61. Chia, J.; Yeo, K.P.; Whisstock, J.C.; Dunstone, M.A.; Trapani, J.A.; Voskoboinik, I. Temperature sensitivity of human perforin mutants unmasks subtotal loss of cytotoxicity, delayed FHL, and a predisposition to cancer. Proc. Natl. Acad. Sci. USA 2009, 106, 9809–9814. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  62. Marcenaro, S.; Gallo, F.; Martini, S.; Santoro, A.; Griffiths, G.M.; Aricò, M.; Moretta, L.; Pende, D. Analysis of natural killer–cell function in familial hemophagocytic lymphohistiocytosis (FHL): Defective CD107a surface expression heralds Munc13-4 defect and discriminates between genetic subtypes of the disease. Blood 2006, 108, 2316–2323. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  63. Soung, Y.H.; Lee, J.W.; Kim, S.Y.; Jang, J.; Park, Y.G.; Park, W.S.; Nam, S.W.; Lee, J.Y.; Yoo, N.J.; Lee, S.H. CASPASE-8 gene is inactivated by somatic mutations in gastric carcinomas. Cancer Res. 2005, 65, 815–821. [Google Scholar] [PubMed]
  64. Liu, B.; Peng, D.; Lu, Y.; Jin, W.; Fan, Z. A Novel Single Amino Acid Deletion Caspase-8 Mutant in Cancer Cells That Lost Proapoptotic Activity. J. Boil. Chem. 2002, 277, 30159–30164. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  65. Soung, Y.H.; Lee, J.W.; Kim, S.Y.; Sung, Y.J.; Park, W.S.; Nam, S.W.; Kim, S.H.; Lee, J.Y.; Yoo, N.J.; Lee, S.H. Caspase-8 gene is frequently inactivated by the frameshift somatic mutation 1225_1226delTG in hepatocellular carcinomas. Oncogene 2004, 24, 141–147. [Google Scholar] [CrossRef] [Green Version]
  66. Lee, J.W.; Kim, M.R.; Soung, Y.H.; Nam, S.W.; Kim, S.H.; Lee, J.Y.; Yoo, N.J.; Lee, S.H. Mutational analysis of the CASP6 gene in colorectal and gastric carcinomas. APMIS 2006, 114, 646–650. [Google Scholar] [CrossRef]
  67. Soung, Y.; Lee, J.; Kim, S.; Park, W.; Nam, S.; Lee, J.; Yoo, N.; Lee, S. Somatic mutations of CASP3 gene in human cancers. Qual. Life Res. 2004, 115, 112–115. [Google Scholar] [CrossRef]
  68. Kim, Y.R.; Kim, K.M.; Yoo, N.J.; Lee, S.H. Mutational analysis of CASP1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and 14 genes in gastrointestinal stromal tumors. Hum. Pathol. 2009, 40, 868–871. [Google Scholar] [CrossRef]
  69. Soung, Y.H.; Jeong, E.G.; Ahn, C.H.; Kim, S.S.; Song, S.Y.; Yoo, N.J.; Lee, S.H. Mutational analysis of caspase 1, 4, and 5 genes in common human cancers. Hum. Pathol. 2008, 39, 895–900. [Google Scholar] [CrossRef]
  70. Soung, Y.H.; Lee, J.W.; Kim, H.S.; Park, W.S.; Kim, S.Y.; Lee, J.-H.; Park, J.Y.; Cho, Y.G.; Kim, C.J.; Park, Y.G.; et al. Inactivating mutations of CASPASE-7 gene in human cancers. Oncogene 2003, 22, 8048–8052. [Google Scholar] [CrossRef] [Green Version]
  71. Soung, Y.H.; Lee, J.W.; Kim, S.Y.; Park, W.S.; Nam, S.W.; Lee, J.Y.; Yoo, N.J.; Lee, S.H. Mutational analysis of proapoptotic caspase-9 gene in common human carcinomas. APMIS 2006, 114, 292–297. [Google Scholar] [CrossRef] [PubMed]
  72. Islam, A.; Kageyama, H.; Takada, N.; Kawamato, T.; Takayasu, H.; Isogai, E.; Ohira, M.; Hashizume, K.; Kobayashi, H.; Kaneko, Y.; et al. High expression of Survivin, mapped to 17q25, is significantly associated with poor prognostic factors and promotes cell survival in human neuroblastoma. Oncogene 2000, 19, 617–623. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  73. Srinivasula, S.M.; Ashwell, J.D. IAPs: What’s in a Name? Mol. Cell 2008, 30, 123–135. [Google Scholar] [CrossRef] [PubMed]
  74. Zender, L.; Spector, M.S.; Xue, W.; Flemming, P.; Cordon-Cardo, C.; Silke, J.; Fan, S.-T.; Luk, J.; Wigler, M.; Hannon, G.J.; et al. Identification and Validation of Oncogenes in Liver Cancer Using an Integrative Oncogenomic Approach. Cell 2006, 125, 1253–1267. [Google Scholar] [CrossRef] [Green Version]
  75. Dierlamm, J.; Baens, M.; Wlodarska, I.; Stefanova-Ouzounova, M.; Hernandez, J.M.; Hossfeld, D.K.; De Wolf-Peeters, C.; Hagemeijer, A.; Berghe, H.V.D.; Marynen, P. The apoptosis inhibitor gene API2 and a novel 18q gene, MLT, are recurrently rearranged in the t(11;18)(q21;q21) associated with mucosa-associated lymphoid tissue lymphomas. Blood 1999, 93, 3601–3609. [Google Scholar] [CrossRef]
  76. Miquel, C.; Borrini, F.; Grandjouan, S.; Aupérin, A.; Viguier, J.; Velasco, V.; Duvillard, P.; Praz, F.; Sabourin, J.-C. Role of bax Mutations in Apoptosis in Colorectal Cancers With Microsatellite Instability. Am. J. Clin. Pathol. 2005, 123, 562–570. [Google Scholar] [CrossRef]
  77. Ionov, Y.; Yamamoto, H.; Krajewski, S.; Reed, J.C.; Perucho, M. Mutational inactivation of the proapoptotic gene BAX confers selective advantage during tumor clonal evolution. Proc. Natl. Acad. Sci. USA 2000, 97, 10872–10877. [Google Scholar] [CrossRef] [Green Version]
  78. Rampino, N.; Yamamoto, H.; Ionov, Y.; Li, Y.; Sawai, H.; Reed, J.C.; Perucho, M. Somatic Frameshift Mutations in theBAXGene in Colon Cancers of the Microsatellite Mutator Phenotype. Science 1997, 275, 967–969. [Google Scholar] [CrossRef]
  79. Inoue, K.; Kohno, T.; Takakura, S.; Hayashi, Y.; Mizoguchi, H.; Yokota, J. Frequent microsatellite instability and BAX mutations in T cell acute lymphoblastic leukemia cell lines. Leuk. Res. 2000, 24, 255–262. [Google Scholar] [CrossRef]
  80. Moshynska, O.; Sankaran, K.; Saxena, A. Molecular detection of the G(−248)A BAX promoter nucleotide change in B cell chronic lymphocytic leukaemia. Mol. Pathol. 2003, 56, 205–209. [Google Scholar] [CrossRef] [Green Version]
  81. Brimmell, M.; Mendiola, R.; Mangion, J.; Packham, G. BAX frameshift mutations in cell lines derived from human haemopoietic malignancies are associated with resistance to apoptosis and microsatellite instability. Oncogene 1998, 16, 1803–1812. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  82. Schuetz, J.M.; A Johnson, N.; Morin, R.D.; Scott, D.W.; Tan, K.; Ben-Nierah, S.; Boyle, M.; Slack, G.W.; A Marra, M.; Connors, J.M.; et al. BCL2 mutations in diffuse large B-cell lymphoma. Leukemia 2011, 26, 1383–1390. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  83. Sarid, R.; Sato, T.; Bohenzky, R.A.; Russo, J.J.; Chang, Y. Kaposi’s sarcoma-associated herpesvirus encodes a functional Bcl-2 homologue. Nat. Med. 1997, 3, 293–298. [Google Scholar] [CrossRef] [PubMed]
  84. Stürzl, M.; Hohenadl, C.; Zietz, C.; Castaños-Vèlez, E.; Wunderlich, A.; Ascherl, G.; Biberfeld, P.; Monini, P.; Browning, P.J.; Ensoli, B. Expression of K13/v-FLIP Gene of Human Herpesvirus 8 and Apoptosis in Kaposi’s Sarcoma Spindle Cells. J. Natl. Cancer Inst. 1999, 91, 1725–1733. [Google Scholar] [CrossRef] [Green Version]
  85. Valnet-Rabier, M.-B.; Challier, B.; Thiébault, S.; Angonin, R.; Margueritte, G.; Mougin, C.; Kantelip, B.; Deconinck, E.; Cahn, J.-Y.; Fest, T. c-Flip protein expression in Burkitt’s lymphomas is associated with a poor clinical outcome. Br. J. Haematol. 2005, 128, 767–773. [Google Scholar] [CrossRef]
  86. McLornan, D.; Hay, J.; McLaughlin, K.; Holohan, C.; Burnett, A.; Hills, R.K.; Johnston, P.G.; Mills, K.I.; McMullin, M.F.; Longley, D.B. Prognostic and therapeutic relevance of c-FLIP in acute myeloid leukaemia. Br. J. Haematol. 2012, 160, 188–198. [Google Scholar] [CrossRef]
  87. Ullenhag, G.J.; Mukherjee, A.; Watson, N.J.; Al-Attar, A.H.; Scholefield, J.H.; Durrant, L. Overexpression of FLIPL Is an Independent Marker of Poor Prognosis in Colorectal Cancer Patients. Clin. Cancer Res. 2007, 13, 5070–5075. [Google Scholar] [CrossRef] [Green Version]
  88. Tagawa, H.; Karnan, S.; Suzuki, R.; Matsuo, K.; Zhang, X.; Ota, A.; Morishima, Y.; Nakamura, S.; Seto, M. Genome-wide array-based CGH for mantle cell lymphoma: Identification of homozygous deletions of the proapoptotic gene BIM. Oncogene 2004, 24, 1348–1358. [Google Scholar] [CrossRef]
  89. Mestre-Escorihuela, C.; Rubio-Moscardó, F.; Richter, J.A.; Siebert, R.; Climent, J.; Fresquet, V.; Beltran, E.; Agirre, X.; Marugan, I.; Mariín, M.; et al. Homozygous deletions localize novel tumor suppressor genes in B-cell lymphomas. Blood 2006, 109, 271–280. [Google Scholar] [CrossRef] [Green Version]
  90. Fisher, M.J.; Virmani, A.K.; Wu, L.; Aplenc, R.; Harper, J.C.; Powell, S.M.; Rebbeck, T.R.; Sidransky, D.; Gazdar, A.F.; El-Deiry, W.S. Nucleotide substitution in the ectodomain of trail receptor DR4 is associated with lung cancer and head and neck cancer. Clin. Cancer Res. 2001, 7, 1688–1697. [Google Scholar]
  91. Lee, S.H.; Shin, M.S.; Kim, H.S.; Lee, H.K.; Park, W.S.; Kim, S.Y.; Lee, J.-H.; Han, S.Y.; Park, J.Y.; Oh, R.R.; et al. Somatic mutations of TRAIL-receptor 1 and TRAIL-receptor 2 genes in non-Hodgkin’s lymphoma. Oncogene 2001, 20, 399–403. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  92. Rubio-Moscardó, F.; Blesa, D.; Mestre, C.; Siebert, R.; Balasas, T.; Benito, A.; Rosenwald, A.; Climent, J.; Martínez, J.I.; Schilhabel, M.; et al. Characterization of 8p21.3 chromosomal deletions in B-cell lymphoma: TRAIL-R1 and TRAIL-R2 as candidate dosage-dependent tumor suppressor genes. Blood 2005, 106, 3214–3222. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  93. Shin, M.S.; Kim, H.S.; Lee, S.H.; Park, W.S.; Kim, S.Y.; Park, J.Y.; Lee, J.H.; Lee, S.K.; Lee, S.N.; Jung, S.S.; et al. Mutations of tumor necrosis factor-related apoptosis-inducing ligand receptor 1 (TRAIL-R1) and receptor 2 (TRAIL-R2) genes in metastatic breast cancers. Cancer Res. 2001, 61, 4942–4946. [Google Scholar] [PubMed]
  94. McDonald, E.R.; Chui, P.C.; Martelli, P.F.; Dicker, D.T.; El-Deiry, W. Death Domain Mutagenesis of KILLER/DR5 Reveals Residues Critical for Apoptotic Signaling. J. Boil. Chem. 2001, 276, 14939–14945. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  95. Lee, S.H.; Shin, M.S.; Kim, H.S.; Lee, H.K.; Park, W.S.; Kim, S.Y.; Lee, J.H.; Han, S.Y.; Park, J.Y.; Oh, R.R.; et al. Alterations of the DR5/TRAIL Receptor 2 Gene in Non-Small Cell Lung Cancers. Cancer Res. 1999, 59, 5683–5686. [Google Scholar] [PubMed]
  96. Park, W.S.; Lee, J.-H.; Shin, M.S.; Park, J.Y.; Kim, H.S.; Kim, Y.S.; Park, C.H.; Lee, S.K.; Lee, S.H.; Lee, S.N.; et al. Inactivating mutations of KILLER/DR5 gene in gastric cancers. Gastroenterol. 2001, 121, 1219–1225. [Google Scholar] [CrossRef]
  97. Tauzin, S.; Debure, L.; Moreau, J.-F.; Legembre, P. CD95-mediated cell signaling in cancer: Mutations and post-translational modulations. Cell. Mol. Life Sci. 2011, 69, 1261–1277. [Google Scholar] [CrossRef]
  98. Shipman, C.M.; I Croucher, P. Osteoprotegerin is a soluble decoy receptor for tumor necrosis factor-related apoptosis-inducing ligand/Apo2 ligand and can function as a paracrine survival factor for human myeloma cells. Cancer Res. 2003, 63, 912–916. [Google Scholar]
  99. Roth, W.; Isenmann, S.; Nakamura, M.; Platten, M.; Wick, W.; Kleihues, P.; Bähr, M.; Ohgaki, H.; Ashkenazi, A.; Weller, M. Soluble decoy receptor 3 is expressed by malignant gliomas and suppresses CD95 ligand-induced apoptosis and chemotaxis. Cancer Res. 2001, 61, 2759–2765. [Google Scholar]
  100. Wu, Q.; Zheng, Y.; Chen, D.; Li, X.; Lu, C.; Zhang, Z.-M. Aberrant expression of decoy receptor 3 in human breast cancer: Relevance to lymphangiogenesis. J. Surg. Res. 2014, 188, 459–465. [Google Scholar] [CrossRef] [Green Version]
  101. Takahama, Y.; Yamada, Y.; Emoto, K.; Fujimoto, H.; Takayama, T.; Ueno, M.; Uchida, H.; Hirao, S.; Mizuno, T.; Nakajima, Y. The prognostic significance of overexpression of the decoy receptor for Fas ligand (DcR3) in patients with gastric carcinomas. Gastric Cancer 2002, 5, 61–68. [Google Scholar] [CrossRef] [PubMed]
  102. Liu, Y.-P.; Zhu, H.-F.; Liu, D.-L.; Hu, Z.-Y.; Li, S.-N.; Kan, H.-P.; Wang, X.-Y.; Li, Z.-G. DcR3 induces epithelial-mesenchymal transition through activation of the TGF-β3/SMAD signaling pathway in CRC. Oncotarget 2016, 7, 77306–77318. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  103. Chamuleau, M.E.; Ossenkoppele, G.; Van Rhenen, A.; Van Dreunen, L.; Jirka, S.; Zevenbergen, A.; Schuurhuis, G.; Van De Loosdrecht, A. High TRAIL-R3 expression on leukemic blasts is associated with poor outcome and induces apoptosis-resistance which can be overcome by targeting TRAIL-R2. Leuk. Res. 2011, 35, 741–749. [Google Scholar] [CrossRef] [Green Version]
  104. De Almodóvar, C.R.; Ruiz-Ruiz, C.; Rodríguez, A.; Ortiz-Ferrón, G.; Redondo, J.M.; Lopez-Rivas, A. Tumor Necrosis Factor-related Apoptosis-inducing Ligand (TRAIL) Decoy Receptor TRAIL-R3 Is Up-regulated by p53 in Breast Tumor Cells through a Mechanism Involving an Intronic p53-binding Site. J. Boil. Chem. 2003, 279, 4093–4101. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  105. Koksal, I.T.; Sanlioglu, A.D.; Karaçay, B.; Griffith, T.S.; Sanlioglu, S. Tumor necrosis factor-related apoptosis inducing ligand-R4 decoy receptor expression is correlated with high Gleason scores, prostate-specific antigen recurrence, and decreased survival in patients with prostate carcinoma. Urol. Oncol. Semin. Orig. Investig. 2008, 26, 158–165. [Google Scholar] [CrossRef]
  106. Peng, Y.-P.; Zhu, Y.; Zhang, J.-J.; Xu, Z.; Qian, Z.; Dai, C.-C.; Jiang, K.-R.; Wu, J.; Gao, W.; Li, Q.; et al. Comprehensive analysis of the percentage of surface receptors and cytotoxic granules positive natural killer cells in patients with pancreatic cancer, gastric cancer, and colorectal cancer. J. Transl. Med. 2013, 11, 262. [Google Scholar] [CrossRef] [Green Version]
  107. Hodge, G.; Barnawi, J.; Jurisevic, C.; Moffat, D.; Holmes, M.; Reynolds, P.N.; Jersmann, H.; Hodge, S. Lung cancer is associated with decreased expression of perforin, granzyme B and interferon (IFN)-γ by infiltrating lung tissue T cells, natural killer (NK) T-like and NK cells. Clin. Exp. Immunol. 2014, 178, 79–85. [Google Scholar] [CrossRef]
  108. Sun, C.; Xu, J.; Huang, Q.; Huang, M.; Wen, H.; Zhang, C.; Wang, J.; Song, J.; Zheng, M.; Sun, H.; et al. High NKG2A expression contributes to NK cell exhaustion and predicts a poor prognosis of patients with liver cancer. Oncoimmunology 2016, 6, e1264562. [Google Scholar] [CrossRef]
  109. Liu, C.; Yu, S.; Kappes, J.; Wang, J.; Grizzle, W.E.; Zinn, K.; Zhang, H.-G. Expansion of spleen myeloid suppressor cells represses NK cell cytotoxicity in tumor-bearing host. Blood 2007, 109, 4336–4342. [Google Scholar] [CrossRef]
  110. Li, T.; Yang, Y.; Hua, X.; Wang, G.; Liu, W.; Jia, C.; Tai, Y.; Zhang, Q.; Chen, G. Hepatocellular carcinoma-associated fibroblasts trigger NK cell dysfunction via PGE2 and IDO. Cancer Lett. 2012, 318, 154–161. [Google Scholar] [CrossRef]
  111. Balsamo, M.; Scordamaglia, F.; Pietra, G.; Manzini, C.; Cantoni, C.; Boitano, M.; Queirolo, P.; Vermi, W.; Facchetti, F.; Moretta, A.; et al. Melanoma-associated fibroblasts modulate NK cell phenotype and antitumor cytotoxicity. Proc. Natl. Acad. Sci. USA 2009, 106, 20847–20852. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  112. Li, T.; Yi, S.; Liu, W.; Jia, C.; Wang, G.; Hua, X.; Tai, Y.; Zhang, Q.; Chen, G. Colorectal carcinoma-derived fibroblasts modulate natural killer cell phenotype and antitumor cytotoxicity. Med Oncol. 2013, 30, 663. [Google Scholar] [CrossRef] [PubMed]
  113. Lehmann, C.; Zeis, M.; Schmitz, N.; Uharek, L. Impaired binding of perforin on the surface of tumor cells is a cause of target cell resistance against cytotoxic effector cells. Blood 2000, 96, 594–600. [Google Scholar] [CrossRef] [PubMed]
  114. Donatelli, S.S.; Zhou, J.-M.; Gilvary, D.L.; Eksioglu, E.A.; Chen, X.; Cress, W.D.; Haura, E.B.; Schabath, M.B.; Coppola, M.; Wei, S.; et al. TGF-β-inducible microRNA-183 silences tumor-associated natural killer cells. Proc. Natl. Acad. Sci. USA 2014, 111, 4203–4208. [Google Scholar] [CrossRef] [Green Version]
  115. Platonova, S.; Cherfils-Vicini, J.; Damotte, D.; Crozet, L.; Vieillard, V.; Validire, P.; Alifano, M.; Sautès-Fridman, C.; Cremer, I.; André, P.; et al. Profound Coordinated Alterations of Intratumoral NK Cell Phenotype and Function in Lung Carcinoma. Cancer Res. 2011, 71, 5412–5422. [Google Scholar] [CrossRef] [Green Version]
  116. Baginska, J.; Viry, E.; Berchem, G.; Poli, A.; Noman, M.Z.; Van Moer, K.; Medves, S.; Zimmer, J.; Oudin, A.; Niclou, S.P.; et al. Granzyme B degradation by autophagy decreases tumor cell susceptibility to natural killer-mediated lysis under hypoxia. Proc. Natl. Acad. Sci. USA 2013, 110, 17450–17455. [Google Scholar] [CrossRef] [Green Version]
  117. Viry, E.; Baginska, J.; Berchem, G.; Noman, M.Z.; Medves, S.; Chouaib, S.; Janji, B. Autophagic degradation of GZMB/granzyme B. Autophagy 2013, 10, 173–175. [Google Scholar] [CrossRef] [Green Version]
  118. Bladergroen, B.A.; Meijer, C.J.L.M.; Berge, R.L.T.; Hack, C.E.; Muris, J.J.F.; Dukers, D.F.; Chott, A.; Kazama, Y.; Oudejans, J.J.; Van Berkum, O.; et al. Expression of the granzyme B inhibitor, protease inhibitor 9, by tumor cells in patients with non-Hodgkin and Hodgkin lymphoma: A novel protective mechanism for tumor cells to circumvent the immune system? Blood 2002, 99, 232–237. [Google Scholar] [CrossRef] [Green Version]
  119. Rousalova, I.; Krepela, E.; Prochazka, J.; Cermak, J.; Benkova, K. Expression of proteinase inhibitor-9/serpinB9 in non-small cell lung carcinoma cells and tissues. Int. J. Oncol. 2010, 36, 275–283. [Google Scholar]
  120. Soriano, C.; Mukaro, V.; Hodge, G.; Ahern, J.; Holmes, M.; Jersmann, H.; Moffat, D.; Meredith, D.; Jurisevic, C.; Reynolds, P.N.; et al. Increased proteinase inhibitor-9 (PI-9) and reduced granzyme B in lung cancer: Mechanism for immune evasion? Lung Cancer 2012, 77, 38–45. [Google Scholar] [CrossRef]
  121. Chechlinska, M.; Kowalewska, M.; Brzoska, E.; Radziszewski, J.; Ptaszyński, K.; Ryś, J.; Kaminska, J.; Nowak, R. Squamous cell carcinoma antigen 1 and 2 expression in cultured normal peripheral blood mononuclear cells and in vulvar squamous cell carcinoma. Tumor Boil. 2010, 31, 559–567. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  122. Cataltepe, S.; Gornstein, E.R.; Schick, C.; Kamachi, Y.; Chatson, K.; Fries, J.; Silverman, G.A.; Upton, M.P. Co-expression of the squamous cell carcinoma antigens 1 and 2 in normal adult human tissues and squamous cell carcinomas. J. Histochem. Cytochem. 2000, 48, 113–122. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  123. Saidak, Z.; Morisse, M.C.; Chatelain, D.; Sauzay, C.; Houessinon, A.; Guilain, N.; Soyez, M.; Chauffert, B.; Dakpe, S.; Galmiche, A. Squamous Cell Carcinoma Antigen-encoding Genes SERPINB3/B4 as Potentially Useful Markers for the Stratification of HNSCC Tumours. Anticancer. Res. 2018, 38, 1343–1352. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  124. Paul, S.; Kulkarni, N.; Shilpi; Lal, G. Intratumoral natural killer cells show reduced effector and cytolytic properties and control the differentiation of effector Th1 cells. Oncoimmunology 2016, 5, e1235106. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  125. Absi, A.A.; Wurzer, H.; Guerin, C.; Hoffmann, C.; Moreau, F.; Mao, X.; Brown-Clay, J.; Petrolli, R.; Casellas, C.P.; Dieterle, M.; et al. Actin Cytoskeleton Remodeling Drives Breast Cancer Cell Escape from Natural Killer–Mediated Cytotoxicity. Cancer Res. 2018, 78, 5631–5643. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  126. Tittarelli, A.; Janji, B.; Van Moer, K.; Noman, M.Z.; Chouaib, S. The Selective Degradation of Synaptic Connexin 43 Protein by Hypoxia-induced Autophagy Impairs Natural Killer Cell-mediated Tumor Cell Killing. J. Boil. Chem. 2015, 290, 23670–23679. [Google Scholar] [CrossRef] [Green Version]
  127. Wensink, A.C.; Hack, C.E.; Bovenschen, N. Granzymes Regulate Proinflammatory Cytokine Responses. J. Immunol. 2015, 194, 491–497. [Google Scholar] [CrossRef] [Green Version]
  128. Voskoboinik, I.; Whisstock, J.C.; Trapani, J.A. Perforin and granzymes: Function, dysfunction and human pathology. Nat. Rev. Immunol. 2015, 15, 388–400. [Google Scholar] [CrossRef]
  129. Bovenschen, N.; Kummer, J.A. Orphan granzymes find a home. Immunol. Rev. 2010, 235, 117–127. [Google Scholar] [CrossRef]
  130. Martinvalet, D.; Dykxhoorn, D.M.; Ferrini, R.; Lieberman, J. Granzyme A Cleaves a Mitochondrial Complex I Protein to Initiate Caspase-Independent Cell Death. Cell 2008, 133, 681–692. [Google Scholar] [CrossRef] [Green Version]
  131. Fan, Z.; Beresford, P.J.; Oh, D.Y.; Zhang, D.; Lieberman, J. Tumor Suppressor NM23-H1 Is a Granzyme A-Activated DNase during CTL-Mediated Apoptosis, and the Nucleosome Assembly Protein SET Is Its Inhibitor. Cell 2003, 112, 659–672. [Google Scholar] [CrossRef] [Green Version]
  132. Martinvalet, D.; Zhu, P.; Lieberman, J. Granzyme A Induces Caspase-Independent Mitochondrial Damage, a Required First Step for Apoptosis. Immun. 2005, 22, 355–370. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  133. Chowdhury, D.; Beresford, P.J.; Zhu, P.; Zhang, N.; Sung, J.-S.; Demple, B.; Perrino, F.W.; Lieberman, J. The Exonuclease TREX1 Is in the SET Complex and Acts in Concert with NM23-H1 to Degrade DNA during Granzyme A-Mediated Cell Death. Mol. Cell 2006, 23, 133–142. [Google Scholar] [CrossRef] [PubMed]
  134. Zhu, P.; Zhang, D.; Chowdhury, D.; Martinvalet, D.; Keefe, D.; Shi, L.; Lieberman, J. Granzyme A, which causes single-stranded DNA damage, targets the double-strand break repair protein Ku70. EMBO Rep. 2006, 7, 431–437. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  135. Zhang, D.; Pasternack, M.S.; Beresford, P.J.; Wagner, L.; Greenberg, A.H.; Lieberman, J. Induction of Rapid Histone Degradation by the Cytotoxic T Lymphocyte Protease Granzyme A. J. Boil. Chem. 2000, 276, 3683–3690. [Google Scholar] [CrossRef] [Green Version]
  136. Beresford, P.J.; Xia, Z.; Greenberg, A.H.; Lieberman, J. Granzyme A Loading Induces Rapid Cytolysis and a Novel Form of DNA Damage Independently of Caspase Activation. Immun. 1999, 10, 585–595. [Google Scholar] [CrossRef] [Green Version]
  137. Rissoan, M.-C.; Duhen, T.; Bridon, J.-M.; Bendriss-Vermare, N.; Péronne, C.; Vis, B.D.S.; Brière, F.; Bates, E.E.M. Subtractive hybridization reveals the expression of immunoglobulinlike transcript 7, Eph-B1, granzyme B, and 3 novel transcripts in human plasmacytoid dendritic cells. Blood 2002, 100, 3295–3303. [Google Scholar] [CrossRef] [Green Version]
  138. Wagner, C.; Iking-Konert, C.; Denefleh, B.; Stegmaier, S.; Hug, F.; Hänsch, G.M. Granzyme B and perforin: Constitutive expression in human polymorphonuclear neutrophils. Blood 2004, 103, 1099–1104. [Google Scholar] [CrossRef] [Green Version]
  139. Tschopp, C.M.; Spiegl, N.; Didichenko, S.; Lutmann, W.; Julius, P.; Virchow, J.C.; Hack, C.E.; Dahinden, C.A. Granzyme B, a novel mediator of allergic inflammation: Its induction and release in blood basophils and human asthma. Blood 2006, 108, 2290–2299. [Google Scholar] [CrossRef]
  140. Strik, M.C.; De Koning, P.J.; Kleijmeer, M.J.; Bladergroen, B.A.; Wolbink, A.M.; Griffith, J.M.; Wouters, D.; Fukuoka, Y.; Schwartz, L.B.; Hack, C.E.; et al. Human mast cells produce and release the cytotoxic lymphocyte associated protease granzyme B upon activation. Mol. Immunol. 2007, 44, 3462–3472. [Google Scholar] [CrossRef]
  141. Trapani, J.A.; Sutton, V.R. Granzyme B: Pro-apoptotic, antiviral and antitumor functions. Curr. Opin. Immunol. 2003, 15, 533–543. [Google Scholar] [CrossRef]
  142. Kelly, J.M.; Waterhouse, N.; Cretney, E.; Browne, K.; Ellis, S.; Trapani, J.A.; Smyth, M.J. Granzyme M Mediates a Novel Form of Perforin-dependent Cell Death. J. Boil. Chem. 2004, 279, 22236–22242. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  143. Bovenschen, N.; De Koning, P.J.A.; Quadir, R.; Broekhuizen, R.; Damen, J.M.A.; Froelich, C.J.; Slijper, M.; Kummer, J.A. NK Cell Protease Granzyme M Targets α-Tubulin and Disorganizes the Microtubule Network. J. Immunol. 2008, 180, 8184–8191. [Google Scholar] [CrossRef] [PubMed]
  144. Pao, L.I.; Sumaria, N.; Kelly, J.M.; Van Dommelen, S.; Cretney, E.; Wallace, M.E.; Anthony, D.A.; Uldrich, A.P.; Godfrey, D.; Papadimitriou, J.M.; et al. Functional Analysis of Granzyme M and Its Role in Immunity to Infection. J. Immunol. 2005, 175, 3235–3243. [Google Scholar] [CrossRef] [Green Version]
  145. Wang, H.; Sun, Q.; Wu, Y.; Wang, L.; Zhou, C.; Ma, W.; Zhang, Y.; Wang, S.; Zhang, S. Granzyme M expressed by tumor cells promotes chemoresistance and EMT in vitro and metastasis in vivo associated with STAT3 activation. Oncotarget 2015, 6, 5818–5831. [Google Scholar] [CrossRef] [Green Version]
  146. Pegram, H.J.; Haynes, N.M.; Smyth, M.J.; Kershaw, M.; Darcy, P.K. Characterizing the anti-tumor function of adoptively transferred NK cells in vivo. Cancer Immunol. Immunother. 2010, 59, 1235–1246. [Google Scholar] [CrossRef]
  147. Mahrus, S.; Kisiel, W.; Craik, C.S. Granzyme M Is a Regulatory Protease That Inactivates Proteinase Inhibitor 9, an Endogenous Inhibitor of Granzyme B. J. Boil. Chem. 2004, 279, 54275–54282. [Google Scholar] [CrossRef] [Green Version]
  148. Davis, J.E.; Smyth, M.J.; Trapani, J.A. Granzyme A and B-deficient killer lymphocytes are defective in eliciting DNA fragmentation but retain potent in vivo anti-tumor capacity. Eur. J. Immunol. 2001, 31, 39–47. [Google Scholar] [CrossRef]
  149. Smyth, M.J.; Street, S.E.A.; Trapani, J.A. Cutting Edge: Granzymes A and B Are Not Essential for Perforin-Mediated Tumor Rejection. J. Immunol. 2003, 171, 515–518. [Google Scholar] [CrossRef] [Green Version]
  150. Revell, P.A.; Grossman, W.J.; Thomas, D.A.; Cao, X.; Behl, R.; Ratner, J.A.; Lu, Z.H.; Ley, T.J. Granzyme B and the downstream granzymes C and/or F are important for cytotoxic lymphocyte functions. J. Immunol. 2005, 174, 2124–2131. [Google Scholar] [CrossRef] [Green Version]
  151. Fehniger, T.A.; Cai, S.; Cao, X.; Bredemeyer, A.J.; Presti, R.; French, A.R.; Ley, T.J. Acquisition of Murine NK Cell Cytotoxicity Requires the Translation of a Pre-existing Pool of Granzyme B and Perforin mRNAs. Immunity 2007, 26, 798–811. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  152. Costa, N.L.; Alencar, R.D.C.G.; Valadares, M.C.; Da Silva, T.A.; De Mendonça, E.F.; Batista, A.C. The clinicopathological significance of the expression of Granzyme B in oral squamous cell carcinoma. Oral Oncol. 2010, 46, 185–189. [Google Scholar] [CrossRef] [PubMed]
  153. Hu, S.X.; Wang, S.; Wang, J.P.; Mills, G.B.; Zhou, Y.; Xu, H.-J. Expression of endogenous granzyme B in a subset of human primary breast carcinomas. Br. J. Cancer 2003, 89, 135–139. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  154. Lindner, S.; Dahlke, K.; Sontheimer, K.; Hagn, M.; Kaltenmeier, C.; Barth, T.F.E.; Beyer, T.; Reister, F.; Fabricius, D.; Lotfi, R.; et al. Interleukin 21-Induced Granzyme B-Expressing B Cells Infiltrate Tumors and Regulate T Cells. Cancer Res. 2013, 73, 2468–2479. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  155. Wieckowski, E.; Wang, G.-Q.; Gastman, B.R.; Goldstein, L.A.; Rabinowich, H. Granzyme B-mediated degradation of T-cell receptor zeta chain. Cancer Res. 2002, 62, 4884–4889. [Google Scholar] [PubMed]
  156. Grossman, W.J.; Verbsky, J.W.; Barchet, W.; Colonna, M.; Atkinson, J.P.; Ley, T.J. Human T Regulatory Cells Can Use the Perforin Pathway to Cause Autologous Target Cell Death. Immun. 2004, 21, 589–601. [Google Scholar] [CrossRef] [Green Version]
  157. Gondek, D.C.; Lu, L.-F.; Quezada, S.A.; Sakaguchi, S.; Noelle, R.J. Cutting Edge: Contact-Mediated Suppression by CD4+CD25+ Regulatory Cells Involves a Granzyme B-Dependent, Perforin-Independent Mechanism. J. Immunol. 2005, 174, 1783–1786. [Google Scholar] [CrossRef] [Green Version]
  158. Salama, P.; Phillips, M.; Platell, C.; Iacopetta, B. Low expression of Granzyme B in colorectal cancer is associated with signs of early metastastic invasion. Histopathol. 2011, 59, 207–215. [Google Scholar] [CrossRef]
  159. Gamen, S.; A Hanson, D.; Kaspar, A.; Naval, J.; Krensky, A.M.; Anel, A. Granulysin-induced apoptosis. I. Involvement of at least two distinct pathways. J. Immunol. 1998, 161, 1758–1764. [Google Scholar]
  160. Krensky, A.M.; Clayberger, C. Biology and clinical relevance of granulysin. Tissue Antigens 2009, 73, 193–198. [Google Scholar] [CrossRef]
  161. Kaspar, A.A.; Okada, S.; Kumar, J.; Poulain, F.R.; Drouvalakis, K.A.; Kelekar, A.; Hanson, D.A.; Kluck, R.M.; Hitoshi, Y.; Johnson, D.E.; et al. A distinct pathway of cell-mediated apoptosis initiated by granulysin. J. Immunol. 2001, 167, 350–356. [Google Scholar] [CrossRef] [PubMed]
  162. Saini, R.; Wilson, C.; Finn, M.W.; Wang, T.; Krensky, A.M.; Clayberger, C. Granulysin Delivered by Cytotoxic Cells Damages Endoplasmic Reticulum and Activates Caspase-7 in Target Cells. J. Immunol. 2011, 186, 3497–3504. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  163. Anderson, D.H.; Sawaya, M.R.; Cascio, D.; Ernst, W.; Modlin, R.L.; Krensky, A.; Eisenberg, D.S. Granulysin crystal structure and a structure-derived lytic mechanism. J. Mol. Boil. 2003, 325, 355–365. [Google Scholar] [CrossRef]
  164. Zhang, H.; Zhong, C.; Shi, L.; Guo, Y.; Fan, Z. Granulysin Induces Cathepsin B Release from Lysosomes of Target Tumor Cells to Attack Mitochondria through Processing of Bid Leading to Necroptosis. J. Immunol. 2009, 182, 6993–7000. [Google Scholar] [CrossRef] [Green Version]
  165. Kitamura, N.; Katagiri, Y.U.; Itagaki, M.; Miyagawa, Y.; Onda, K.; Okita, H.; Mori, A.; Fujimoto, J.; Kiyokawa, N. The expression of granulysin in systemic anaplastic large cell lymphoma in childhood. Leuk. Res. 2009, 33, 908–912. [Google Scholar] [CrossRef]
  166. Saigusa, S.; Ichikura, T.; Tsujimoto, H.; Sugasawa, H.; Majima, T.; Kawarabayashi, N.; Chochi, K.; Ono, S.; Kinoshita, M.; Seki, S.; et al. Serum granulysin level as a novel prognostic marker in patients with gastric carcinoma. J. Gastroenterol. Hepatol. 2007, 22, 1322–1327. [Google Scholar] [CrossRef]
  167. Bruno, M.E.; Kaiser, A.; Montville, T.J. Depletion of proton motive force by nisin in Listeria monocytogenes cells. Appl. Environ. Microbiol. 1992, 58, 2255–2259. [Google Scholar] [CrossRef] [Green Version]
  168. Kishi, A.; Takamori, Y.; Ogawa, K.; Takano, S.; Tomita, S.; Tanigawa, M.; Niman, M.; Kishida, T.; Fujita, S. Differential expression of granulysin and perforin by NK cells in cancer patients and correlation of impaired granulysin expression with progression of cancer. Cancer Immunol. Immunother. 2002, 50, 604–614. [Google Scholar] [CrossRef]
  169. Furudate, S.; Fujimura, T.; Kambayashi, Y.; Aiba, S. Profiles of Cytotoxic T Lymphocytes in Cutaneous Lymphoid Hyperplasia of the Face. Case Rep. Dermatol. 2013, 5, 88–92. [Google Scholar] [CrossRef]
  170. Bello, G.L.; Akarca, A.U.; Ambrosio, M.R.; Agostinelli, C.; Molina-Kirsch, H.; Ramsay, A.; Rodriguez-Justo, M.; Pugh, M.; Zhao, S.; Delisser, M.; et al. Granulysin, a novel marker for extranodal NK/T cell lymphoma, nasal type. Virchows Arch. 2018, 473, 749–757. [Google Scholar] [CrossRef] [Green Version]
  171. Aporta, A.; Catalán, E.; Galan-Malo, P.; Ramirez-Labrada, A.G.; Pérez, M.; Azaceta, G.; Palomera, L.; Naval, J.; Marzo, I.; Pardo, J.; et al. Granulysin induces apoptotic cell death and cleavage of the autophagy regulator Atg5 in human hematological tumors. Biochem. Pharmacol. 2014, 87, 410–423. [Google Scholar] [CrossRef] [PubMed]
  172. Al-Wasaby, S.; De Miguel, D.; Aporta, A.; Naval, J.; Conde, B.; Martinez-Lostao, L.; Anel, A. In vivo potential of recombinant granulysin against human tumors. Oncoimmunology 2015, 4, e1036213. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  173. Ibáñez-Pérez, R.; Guerrero-Ochoa, P.; Al-Wasaby, S.; Navarro, R.; Tapia-Galisteo, A.; De Miguel, D.; Gonzalo, O.; Conde, B.; Martínez-Lostao, L.; Hurtado-Guerrero, R.; et al. Anti-tumoral potential of a human granulysin-based, CEA-targeted cytolytic immunotoxin. Oncoimmunology 2019, 8, 1641392. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  174. Stupack, D.G. Caspase-8 as a therapeutic target in cancer. Cancer Lett. 2010, 332, 133–140. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  175. Dagbay, K.B.; Hill, M.E.; Barrett, E.; Hardy, J.A. Tumor-Associated Mutations in Caspase-6 Negatively Impact Catalytic Efficiency. Biochem. 2017, 56, 4568–4577. [Google Scholar] [CrossRef]
  176. Hosokawa, Y.; Suzuki, H.; Takahashi, R.; Seto, M. Antiapoptotic Function of Apoptosis Inhibitor 2-MALT1 Fusion Protein Involved in t(11;18)(q21;q21) Mucosa-Associated Lymphoid Tissue Lymphoma. Cancer Res. 2004, 64, 3452–3457. [Google Scholar] [CrossRef] [Green Version]
  177. Stoffel, A.; Chaurushiya, M.; Singh, B.; Levine, A.J. Activation of NF-κB and inhibition of p53-mediated apoptosis by API2/mucosa-associated lymphoid tissue 1 fusions promote oncogenesis. Proc. Natl. Acad. Sci. USA 2004, 101, 9079–9084. [Google Scholar] [CrossRef] [Green Version]
  178. Yamamoto, H.; Gil, J.; Schwartz, S.; Perucho, M. Frameshift mutations in Fas, Apaf-1, and Bcl-10 in gastro-intestinal cancer of the microsatellite mutator phenotype. Cell Death Differ. 2000, 7, 238–239. [Google Scholar] [CrossRef]
  179. Stolz, C.; Hess, G.; Hähnel, P.S.; Grabellus, F.; Hoffarth, S.; Schmid, K.W.; Schuler, M. Targeting Bcl-2 family proteins modulates the sensitivity of B-cell lymphoma to rituximab-induced apoptosis. Blood 2008, 112, 3312–3321. [Google Scholar] [CrossRef]
  180. Wobser, M.; Voigt, H.; O Eggert, A.; Houben, R.; Kauczok, C.S.; Bröcker, E.B.; Becker, J.C. Bcl-2 expression in rituximab refractory cutaneous B-cell lymphoma. Br. J. Cancer 2007, 96, 1540–1543. [Google Scholar] [CrossRef]
  181. Bin, L.; Thorburn, J.; Thomas, L.R.; Clark, P.E.; Humphreys, R.; Thorburn, A. Tumor-derived Mutations in the TRAIL Receptor DR5 Inhibit TRAIL Signaling through the DR4 Receptor by Competing for Ligand Binding. J. Boil. Chem. 2007, 282, 28189–28194. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  182. Qin, L.X.; Tang, Z.-Y.; Sham, J.S.; Ma, Z.C.; Ye, S.L.; Zhou, X.D.; Wu, Z.Q.; Trent, J.M.; Guan, X.Y. The association of chromosome 8p deletion and tumor metastasis in human hepatocellular carcinoma. Cancer Res. 1999, 59, 5662–5665. [Google Scholar] [PubMed]
  183. Cai, Y.; Crowther, J.; Pastor, T.; Asbagh, L.A.; Baietti, M.F.; De Troyer, M.; Vazquez, I.; Talebi, A.; Renzi, F.; Dehairs, J.; et al. Loss of Chromosome 8p Governs Tumor Progression and Drug Response by Altering Lipid Metabolism. Cancer Cell 2016, 29, 751–766. [Google Scholar] [CrossRef] [PubMed]
  184. Kluth, M.; Amschler, N.N.; Galal, R.; Möller-Koop, C.; Barrow, P.; Tsourlakis, M.C.; Jacobsen, F.; Hinsch, A.; Wittmer, C.; Steurer, S.; et al. Deletion of 8p is an independent prognostic parameter in prostate cancer. Oncotarget 2016, 8, 379–392. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  185. Eichenauer, T.; Bannenberg, D.C.; Kluth, M.; Wittmer, C.; Büscheck, F.; Möller, K.; Dum, D.; Fraune, C.; Hube-Magg, C.; Möller-Koop, C.; et al. 8p deletions in renal cell carcinoma are associated with unfavorable tumor features and poor overall survival. Urol. Oncol. Semin. Orig. Investig. 2020, 38, 43.e13-43.e20. [Google Scholar] [CrossRef]
  186. Luebke, T.; Schwarz, L.; Beer, Y.Y.; Schumann, S.; Misterek, M.; Sander, F.E.; Plaza-Sirvent, C.; Schmitz, I. c-FLIP and CD95 signaling are essential for survival of renal cell carcinoma. Cell Death Dis. 2019, 10, 384. [Google Scholar] [CrossRef] [Green Version]
  187. Zheng, H.; Zhang, Y.; Zhan, Y.; Liu, S.; Lu, J.; Wen, Q.; Fan, S. Expression of DR5 and c-FLIP proteins as novel prognostic biomarkers for non-small cell lung cancer patients treated with surgical resection and chemotherapy. Oncol. Rep. 2019, 42, 2363–2370. [Google Scholar] [CrossRef]
  188. Lee, S.; Yoon, C.Y.; Byun, S.-S.; Lee, E.; Lee, S.E. The Role of c-FLIP in Cisplatin Resistance of Human Bladder Cancer Cells. J. Urol. 2013, 189, 2327–2334. [Google Scholar] [CrossRef]
  189. Alkurdi, L.; Virard, F.; Vanbervliet, B.; Weber, K.; Toscano, F.; Bonnin, M.; Le Stang, N.; Lantuejoul, S.; Micheau, O.; Renno, T.; et al. Release of c-FLIP brake selectively sensitizes human cancer cells to TLR3-mediated apoptosis. Cell Death Dis. 2018, 9, 874. [Google Scholar] [CrossRef]
  190. Longley, D.B.; Wilson, T.R.; McEwan, M.; Allen, W.L.; McDermott, M.W.; Galligan, L.; Johnston, P.G. c-FLIP inhibits chemotherapy-induced colorectal cancer cell death. Oncogene 2005, 25, 838–848. [Google Scholar] [CrossRef] [Green Version]
  191. Kataoka, T.; Schröter, M.; Hahne, M.; Schneider, P.; Irmler, M.; Thome, M.; Froelich, C.J.; Tschopp, J. FLIP prevents apoptosis induced by death receptors but not by perforin/granzyme B, chemotherapeutic drugs, and gamma irradiation. J. Immunol. 1998, 161, 3936–3942. [Google Scholar] [PubMed]
  192. Taylor, M.A.; Chaudhary, P.M.; Klem, J.; Kumar, V.; Schatzle, J.D.; Bennett, M. Inhibition of the death receptor pathway by cFLIP confers partial engraftment of MHC class I-deficient stem cells and reduces tumor clearance in perforin-deficient mice. J. Immunol. 2001, 167, 4230–4237. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  193. Krueger, A.; Schmitz, I.; Baumann, S.; Krammer, P.H.; Kirchhoff, S. Cellular FLICE-inhibitory Protein Splice Variants Inhibit Different Steps of Caspase-8 Activation at the CD95 Death-inducing Signaling Complex. J. Boil. Chem. 2001, 276, 20633–20640. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  194. Golks, A.; Brenner, D.; Fritsch, C.; Krammer, P.H.; Lavrik, I.N. c-FLIPR, a New Regulator of Death Receptor-induced Apoptosis. J. Boil. Chem. 2005, 280, 14507–14513. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  195. Chang, D.W.; Xing, Z.; Pan, Y.; Algeciras-Schimnich, A.; Barnhart, B.C.; Yaish-Ohad, S.; Peter, M.E.; Yang, X. c-FLIPL is a dual function regulator for caspase-8 activation and CD95-mediated apoptosis. EMBO J. 2002, 21, 3704–3714. [Google Scholar] [CrossRef]
  196. Zhang, H.; Chen, X.; Li, N.; Cui, L.; Ye, X.; Wan, X. DcR3 promotes hepatoma cell migration by downregulating E-cadherin expression. Oncol. Rep. 2017, 38, 377–383. [Google Scholar] [CrossRef] [Green Version]
  197. Ge, H.; Liang, C.; Li, Z.; An, D.; Ren, S.; Yue, C.; Wu, J. DcR3 induces proliferation, migration, invasion, and EMT in gastric cancer cells via the PI3K/AKT/GSK-3β/β-catenin signaling pathway. Onco. Targets Ther. 2018, 11, 4177–4187. [Google Scholar] [CrossRef] [Green Version]
  198. Ganten, T.M.; Sykora, J.; Koschny, R.; Batke, E.; Aulmann, S.; Mansmann, U.; Stremmel, W.; Sinn, H.-P.; Walczak, H. Prognostic significance of tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor expression in patients with breast cancer. J. Mol. Med. 2009, 87, 995–1007. [Google Scholar] [CrossRef]
  199. Sanlioglu, A.D.; Dirice, E.; Elpek, O.; Korcum, A.F.; Ozdogan, M.; Süleymanlar, I.; Balcı, M.K.; Griffith, T.S.; Sanlioglu, S. High TRAIL Death Receptor 4 and Decoy Receptor 2 Expression Correlates With Significant Cell Death in Pancreatic Ductal Adenocarcinoma Patients. Pancreas 2009, 38, 154–160. [Google Scholar] [CrossRef] [Green Version]
  200. Yang, J.; Leblanc, F.; Dighe, S.A.; Hamele, C.E.; Olson, T.; Feith, D.J.; Loughran, T.P. TRAIL mediates and sustains constitutive NF-κB activation in LGL leukemia. Blood 2018, 131, 2803–2815. [Google Scholar] [CrossRef]
  201. Degli-Esposti, M.A.; Dougall, W.C.; Smolak, P.J.; Waugh, J.Y.; Smith, C.A.; Goodwin, R.G. The novel receptor TRAIL-R4 induces NF-kappaB and protects against TRAIL-mediated apoptosis, yet retains an incomplete death domain. Immunity 1997, 7, 813–820. [Google Scholar] [CrossRef] [Green Version]
  202. Chen, L.; Park, S.-M.; Tumanov, A.V.; Hau, A.; Sawada, K.; Feig, C.; Turner, J.R.; Fu, Y.-X.; Romero, I.L.; Lengyel, E.; et al. CD95 promotes tumour growth. Nature 2010, 465, 492–496. [Google Scholar] [CrossRef] [PubMed]
  203. Ceppi, P.; Hadji, A.; Kohlhapp, F.J.; Pattanayak, A.; Hau, A.; Liu, X.; Liu, H.; Murmann, A.E.; Peter, M.E. CD95 and CD95L promote and protect cancer stem cells. Nat. Commun. 2014, 5, 5238. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  204. Peter, M.E. DICE. Cell Cycle 2014, 13, 1373–1378. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  205. Walczak, H.; Miller, R.E.; Ariail, K.; Gliniak, B.; Griffith, T.S.; Kubin, M.; Chin, W.; Jones, J.; Woodward, A.; Le, T.; et al. Tumoricidal activity of tumor necrosis factor–related apoptosis–inducing ligand in vivo. Nat. Med. 1999, 5, 157–163. [Google Scholar] [CrossRef]
  206. Ashkenazi, A.; Pai, R.C.; Fong, S.; Leung, S.; Lawrence, D.A.; Marsters, S.A.; Blackie, C.; Chang, L.; McMurtrey, A.E.; Hebert, A.; et al. Safety and antitumor activity of recombinant soluble Apo2 ligand. J. Clin. Investig. 1999, 104, 155–162. [Google Scholar] [CrossRef]
  207. Ouyang, X.; Shi, M.; Jie, F.; Bai, Y.; Shen, P.; Yu, Z.; Wang, X.; Huang, C.; Tao, M.; Wang, Z.; et al. Phase III study of dulanermin (recombinant human tumor necrosis factor-related apoptosis-inducing ligand/Apo2 ligand) combined with vinorelbine and cisplatin in patients with advanced non-small-cell lung cancer. Investig. New Drugs 2017, 36, 315–322. [Google Scholar] [CrossRef]
  208. Han, H.R.; Park, S.A.; Ahn, S.; Jeun, S.-S.; Ryu, C.H. Evaluation of Combination Treatment Effect With TRAIL-secreting Mesenchymal Stem Cells and Compound C Against Glioblastoma. Anticancer. Res. 2019, 39, 6635–6643. [Google Scholar] [CrossRef]
  209. Eng, J.W.-L.; Mace, T.A.; Sharma, R.; Twum, D.Y.F.; Peng, P.; Gibbs, J.F.; Pitoniak, R.; Reed, C.B.; Abrams, S.I.; Repasky, E.A.; et al. Pancreatic cancer stem cells in patient pancreatic xenografts are sensitive to drozitumab, an agonistic antibody against DR5. J. Immunother. Cancer 2016, 4, 33. [Google Scholar] [CrossRef] [Green Version]
  210. Dine, J.L.; O’Sullivan, C.C.; Voeller, D.; Greer, Y.E.; Chavez, K.J.; Conway, C.M.; Sinclair, S.; Stone, B.; Amiri-Kordestani, L.; Merchant, A.S.; et al. The TRAIL receptor agonist drozitumab targets basal B triple-negative breast cancer cells that express vimentin and Axl. Breast Cancer Res. Treat. 2016, 155, 235–251. [Google Scholar] [CrossRef] [Green Version]
  211. Cheah, C.Y.; Belada, D.; Fanale, M.A.; Janikova, A.; Czucman, M.S.; Flinn, I.W.; Kapp, A.V.; Ashkenazi, A.; Kelley, S.; Bray, G.L.; et al. Dulanermin with rituximab in patients with relapsed indolent B-cell lymphoma: An open-label phase 1b/2 randomised study. Lancet Haematol. 2015, 2, e166–e174. [Google Scholar] [CrossRef]
  212. Soria, J.-C.; Márk, Z.; Zatloukal, P.; Szima, B.; Albert, I.; Juhász, E.; Pujol, J.-L.; Kozielski, J.; Baker, N.; Smethurst, D.; et al. Randomized Phase II Study of Dulanermin in Combination With Paclitaxel, Carboplatin, and Bevacizumab in Advanced Non–Small-Cell Lung Cancer. J. Clin. Oncol. 2011, 29, 4442–4451. [Google Scholar] [CrossRef] [PubMed]
  213. Rocha-Lima, C.M.; Bayraktar, S.; Flores, A.M.; MacIntyre, J.; Montero, A.; Baranda, J.C.; Wallmark, J.; Portera, C.; Raja, R.; Stern, H.; et al. Phase Ib Study of Drozitumab Combined With First-Line mFOLFOX6 Plus Bevacizumab in Patients with Metastatic Colorectal Cancer. Cancer Investig. 2012, 30, 727–731. [Google Scholar] [CrossRef] [PubMed]
  214. Von Pawel, J.; Harvey, J.H.; Spigel, D.R.; Dediu, M.; Reck, M.; Cebotaru, C.L.; Humphreys, R.C.; Gribbin, M.J.; Fox, N.L.; Camidge, D.R. Phase II Trial of Mapatumumab, a Fully Human Agonist Monoclonal Antibody to Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Receptor 1 (TRAIL-R1), in Combination With Paclitaxel and Carboplatin in Patients With Advanced Non–Small-Cell Lung Cancer. Clin. Lung Cancer 2014, 15, 188–196.e2. [Google Scholar] [CrossRef]
  215. Paz-Ares, L.; Bálint, B.; De Boer, R.H.; Van Meerbeeck, J.P.; Wierzbicki, R.; De Souza, P.; Galimi, F.; Haddad, V.; Sabin, T.; Hei, Y.-J.; et al. A Randomized Phase 2 Study of Paclitaxel and Carboplatin with or without Conatumumab for First-Line Treatment of Advanced Non–Small-Cell Lung Cancer. J. Thorac. Oncol. 2013, 8, 329–337. [Google Scholar] [CrossRef] [Green Version]
  216. Forero-Torres, A.; Infante, J.R.; Waterhouse, D.; Wong, L.; Vickers, S.; Arrowsmith, E.; He, A.R.; Hart, L.; Trent, D.; Wade, J.; et al. Phase 2, multicenter, open-label study of tigatuzumab (CS-1008), a humanized monoclonal antibody targeting death receptor 5, in combination with gemcitabine in chemotherapy-naive patients with unresectable or metastatic pancreatic cancer. Cancer Med. 2013, 2, 925–932. [Google Scholar] [CrossRef]
  217. Macfarlane, M.; Inoue, S.; Kohlhaas, S.L.; Majid, A.; Harper, N.; Kennedy, D.B.J.; Dyer, M.J.; Cohen, G.M. Chronic lymphocytic leukemic cells exhibit apoptotic signaling via TRAIL-R1. Cell Death Differ. 2005, 12, 773–782. [Google Scholar] [CrossRef]
  218. O’Leary, L.; Van Der Sloot, A.M.; Reis, C.R.; Deegan, S.; Ryan, A.; Dhami, S.P.S.; Murillo, L.S.; Cool, R.; De Sampaio, P.C.; Thompson, K.; et al. Decoy receptors block TRAIL sensitivity at a supracellular level: The role of stromal cells in controlling tumour TRAIL sensitivity. Oncogene 2015, 35, 1261–1270. [Google Scholar] [CrossRef]
  219. Kelley, R.F.; Totpal, K.; Lindstrom, S.H.; Mathieu, M.; Billeci, K.; Deforge, L.; Pai, R.; Hymowitz, S.G.; Ashkenazi, A. Receptor-selective Mutants of Apoptosis-inducing Ligand 2/Tumor Necrosis Factor-related Apoptosis-inducing Ligand Reveal a Greater Contribution of Death Receptor (DR) 5 than DR4 to Apoptosis Signaling. J. Boil. Chem. 2004, 280, 2205–2212. [Google Scholar] [CrossRef] [Green Version]
  220. Macfarlane, M.; Kohlhaas, S.L.; Sutcliffe, M.; Dyer, M.J.; Cohen, G.M. TRAIL Receptor-Selective Mutants Signal to Apoptosis via TRAIL-R1 in Primary Lymphoid Malignancies. Cancer Res. 2005, 65, 11265–11270. [Google Scholar] [CrossRef] [Green Version]
  221. Lemke, J.; Von Karstedt, S.; Zinngrebe, J.; Walczak, H. Getting TRAIL back on track for cancer therapy. Cell Death Differ. 2014, 21, 1350–1364. [Google Scholar] [CrossRef] [Green Version]
  222. Lawrence, D.; Shahrokh, Z.; Marsters, S.; Achilles, K.; Shih, D.; Mounho, B.; Hillan, K.; Totpal, K.; Deforge, L.; Schow, P.; et al. Differential hepatocyte toxicity of recombinant Apo2L/TRAIL versions. Nat. Med. 2001, 7, 383–385. [Google Scholar] [CrossRef]
  223. Ganten, T.M.; Koschny, R.; Sykora, J.; Schulze-Bergkamen, H.; Büchler, P.; Haas, T.; Schader, M.B.; Untergasser, A.; Stremmel, W.; Walczak, H. Preclinical Differentiation between Apparently Safe and Potentially Hepatotoxic Applications of TRAIL Either Alone or in Combination with Chemotherapeutic Drugs. Clin. Cancer Res. 2006, 12, 2640–2646. [Google Scholar] [CrossRef] [Green Version]
  224. Nihira, K.; Nan-Ya, K.-I.; Kakuni, M.; Ono, Y.; Yoshikawa, Y.; Ota, T.; Hiura, M.; Yoshinari, K. Chimeric Mice With Humanized Livers Demonstrate Human-Specific Hepatotoxicity Caused by a Therapeutic Antibody Against TRAIL-Receptor 2/Death Receptor 5. Toxicol. Sci. 2018, 167, 190–201. [Google Scholar] [CrossRef] [Green Version]
  225. Papadopoulos, K.P.; Isaacs, R.; Bilic, S.; Kentsch, K.; Huet, H.A.; Hofmann, M.; Rasco, D.; Kundamal, N.; Tang, Z.; Cooksey, J.; et al. Unexpected hepatotoxicity in a phase I study of TAS266, a novel tetravalent agonistic Nanobody® targeting the DR5 receptor. Cancer Chemother. Pharmacol. 2015, 75, 887–895. [Google Scholar] [CrossRef]
  226. Lemke, J.; Von Karstedt, S.; El Hay, M.A.; Conti, A.; Arce, F.; Montinaro, A.; Papenfuss, K.; A El-Bahrawy, M.; Walczak, H. Selective CDK9 inhibition overcomes TRAIL resistance by concomitant suppression of cFlip and Mcl-1. Cell Death Differ. 2013, 21, 491–502. [Google Scholar] [CrossRef]
  227. Gallouet, A.-S.; Travert, M.; Bresson-Bepoldin, L.; Guilloton, F.; Pangault, C.; Caulet-Maugendre, S.; Lamy, T.; Tarte, K.; Guillaudeux, T. COX-2-Independent Effects of Celecoxib Sensitize Lymphoma B Cells to TRAIL-Mediated Apoptosis. Clin. Cancer Res. 2014, 20, 2663–2673. [Google Scholar] [CrossRef] [Green Version]
  228. Lu, J.; McEachern, N.; Sun, H.; Bai, L.; Peng, Y.; Qiu, S.; Miller, R.; Liao, J.; Yi, H.; Liu, M.; et al. Therapeutic potential and molecular mechanism of a novel, potent, nonpeptide, Smac mimetic SM-164 in combination with TRAIL for cancer treatment. Mol. Cancer Ther. 2011, 10, 902–914. [Google Scholar] [CrossRef] [Green Version]
  229. Fulda, S. Promises and Challenges of Smac Mimetics as Cancer Therapeutics. Clin. Cancer Res. 2015, 21, 5030–5036. [Google Scholar] [CrossRef] [Green Version]
  230. Jo, E.B.; Lee, Y.S.; Lee, H.; Park, J.B.; Park, H.; Choi, Y.-L.; Hong, D.; Kim, S.J. Combination therapy with c-met inhibitor and TRAIL enhances apoptosis in dedifferentiated liposarcoma patient-derived cells. BMC Cancer 2019, 19, 496. [Google Scholar] [CrossRef] [Green Version]
  231. Rodriguez, G.-; Villa-Álvarez, M.; Bahamonde, S.-; Herrero, L.-; Gonzalez, S.; Gonzalez, A.P.; Sordo-Bahamonde, C.; Lorenzo-Herrero, S. NK Cells in the Treatment of Hematological Malignancies. J. Clin. Med. 2019, 8, 1557. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  232. Sordo-Bahamonde, C.; Vitale, M.; Lorenzo-Herrero, S.; López-Soto, A.; Gonzalez, S. Mechanisms of Resistance to NK Cell Immunotherapy. Cancers 2020, 12, 893. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  233. Rudnick, S.I.; Lou, J.; Shaller, C.C.; Tang, Y.; Klein-Szanto, A.J.; Weiner, L.M.; Marks, J.D.; Adams, G.P. Influence of Affinity and Antigen Internalization on the Uptake and Penetration of Anti-HER2 Antibodies in Solid Tumors. Cancer Res. 2011, 71, 2250–2259. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  234. Liu, C.; Yu, S.; Zinn, K.; Wang, J.; Zhang, L.; Jia, Y.; Kappes, J.C.; Barnes, S.; Kimberly, R.; Grizzle, W.E.; et al. Murine mammary carcinoma exosomes promote tumor growth by suppression of NK cell function. J. Immunol. 2006, 176, 1375–1385. [Google Scholar] [CrossRef] [Green Version]
  235. Jun, E.; Song, A.Y.; Choi, J.-W.; Lee, H.H.; Kim, M.-Y.; Ko, D.-H.; Kang, H.J.; Kim, S.W.; Bryceson, Y.; Kim, S.C.; et al. Progressive Impairment of NK Cell Cytotoxic Degranulation Is Associated With TGF-β1 Deregulation and Disease Progression in Pancreatic Cancer. Front. Immunol. 2019, 10, 1354. [Google Scholar] [CrossRef]
  236. Bird, C.H.; Sutton, V.R.; Sun, J.; Hirst, C.; Novak, A.; Kumar, S.; Trapani, J.A.; Bird, P. Selective Regulation of Apoptosis: The Cytotoxic Lymphocyte Serpin Proteinase Inhibitor 9 Protects against Granzyme B-Mediated Apoptosis without Perturbing the Fas Cell Death Pathway. Mol. Cell. Boil. 1998, 18, 6387–6398. [Google Scholar] [CrossRef] [Green Version]
  237. Medema, J.P.; De Jong, J.; Peltenburg, L.T.C.; Verdegaal, E.M.E.; Gorter, A.; Bres, S.A.; Franken, K.L.M.C.; Hahne, M.; Albar, J.P.; Melief, C.J.M.; et al. Blockade of the granzyme B/perforin pathway through overexpression of the serine protease inhibitor PI-9/SPI-6 constitutes a mechanism for immune escape by tumors. Proc. Natl. Acad. Sci. USA 2001, 98, 11515–11520. [Google Scholar] [CrossRef] [Green Version]
  238. De Koning, P.J.A.; Kummer, J.A.; De Poot, S.A.H.; Quadir, R.; Broekhuizen, R.; McGettrick, A.F.; Higgins, W.J.; Devreese, B.; Worrall, D.M.; Bovenschen, N. Intracellular Serine Protease Inhibitor SERPINB4 Inhibits Granzyme M-Induced Cell Death. PLoS ONE 2011, 6, e22645. [Google Scholar] [CrossRef]
  239. Aydin, E.; Johansson, J.; Nazir, F.H.; Martner, A.; Hellstrand, K. Role of NOX2-Derived Reactive Oxygen Species in NK Cell–Mediated Control of Murine Melanoma Metastasis. Cancer Immunol. Res. 2017, 5, 804–811. [Google Scholar] [CrossRef] [Green Version]
  240. Mellqvist, U.H.; Hansson, M.; Brune, M.; Dahlgren, C.; Hermodsson, S.; Hellstrand, K. Natural killer cell dysfunction and apoptosis induced by chronic myelogenous leukemia cells: Role of reactive oxygen species and regulation by histamine. Blood 2000, 96, 1961–1968. [Google Scholar] [CrossRef]
  241. Romero, A.I.; Thorén, F.B.; Brune, M.; Hellstrand, K. NKp46 and NKG2D receptor expression in NK cells with CD56dim and CD56bright phenotype: Regulation by histamine and reactive oxygen species. Br. J. Haematol. 2006, 132, 91–98. [Google Scholar] [CrossRef] [PubMed]
  242. Balsamo, M.; Manzini, C.; Pietra, G.; Raggi, F.; Blengio, F.; Mingari, M.C.; Varesio, L.; Moretta, L.; Bosco, M.C.; Vitale, M. Hypoxia downregulates the expression of activating receptors involved in NK-cell-mediated target cell killing without affecting ADCC. Eur. J. Immunol. 2013, 43, 2756–2764. [Google Scholar] [CrossRef]
  243. Sceneay, J.; Chow, M.T.; Chen, A.; Halse, H.M.; Wong, C.S.; Andrews, D.; Sloan, E.K.; Parker, B.S.; Bowtell, D.; Smyth, M.J.; et al. Primary Tumor Hypoxia Recruits CD11b+/Ly6Cmed/Ly6G+Immune Suppressor Cells and Compromises NK Cell Cytotoxicity in the Premetastatic Niche. Cancer Res. 2012, 72, 3906–3911. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  244. Melaiu, O.; Lucarini, V.; Cifaldi, L.; Fruci, D. Influence of the Tumor Microenvironment on NK Cell Function in Solid Tumors. Front. Immunol. 2020, 10, 3038. [Google Scholar] [CrossRef] [PubMed]
  245. Chiu, D.K.-C.; Xu, I.M.-J.; Lai, R.K.-H.; Tse, A.P.-W.; Wei, L.L.; Koh, H.-Y.; Li, L.L.; Lee, D.; Lo, C.L.R.; Wong, C.-M.; et al. Hypoxia induces myeloid-derived suppressor cell recruitment to hepatocellular carcinoma through chemokine (C-C motif) ligand 26. Hepatol. 2016, 64, 797–813. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  246. Henze, A.-T.; Mazzone, M. The impact of hypoxia on tumor-associated macrophages. J. Clin. Investig. 2016, 126, 3672–3679. [Google Scholar] [CrossRef] [PubMed]
  247. Facciabene, A.; Peng, X.; Hagemann, I.S.; Balint, K.; Barchetti, A.; Wang, L.-P.; Gimotty, P.A.; Gilks, C.B.; Lal, P.; Zhang, L.; et al. Tumour hypoxia promotes tolerance and angiogenesis via CCL28 and Treg cells. Nature 2011, 475, 226–230. [Google Scholar] [CrossRef]
  248. Ghiringhelli, F.; Menard, C.; Terme, M.; Flament, C.; Taieb, J.; Chaput, N.; Puig, P.E.; Novault, S.; Escudier, B.; Vivier, E.; et al. CD4+CD25+ regulatory T cells inhibit natural killer cell functions in a transforming growth factor-beta-dependent manner. J. Exp. Med. 2005, 202, 1075–1085. [Google Scholar] [CrossRef] [PubMed]
  249. Trotta, R.; Col, J.D.; Yu, J.; Ciarlariello, D.; Thomas, B.; Zhang, X.; Allard, J.; Wei, M.; Mao, H.; Byrd, J.C.; et al. TGF-β Utilizes SMAD3 to Inhibit CD16-Mediated IFN-γ Production and Antibody-Dependent Cellular Cytotoxicity in Human NK Cells1. J. Immunol. 2008, 181, 3784–3792. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  250. Lee, J.-C.; Lee, K.-M.; Kim, D.-W.; Heo, D.S. Elevated TGF-β1 Secretion and Down-Modulation of NKG2D Underlies Impaired NK Cytotoxicity in Cancer Patients. J. Immunol. 2004, 172, 7335–7340. [Google Scholar] [CrossRef] [PubMed]
  251. Lazarova, M.; Steinle, A. Impairment of NKG2D-Mediated Tumor Immunity by TGF-β. Front. Immunol. 2019, 10, 2689. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  252. Li, H.; Han, Y.; Guo, Q.; Zhang, M.; Cao, X. Cancer-Expanded Myeloid-Derived Suppressor Cells Induce Anergy of NK Cells through Membrane-Bound TGF-β1. J. Immunol. 2008, 182, 240–249. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  253. Corzo, C.A.; Cotter, M.J.; Cheng, P.; Cheng, F.; Kusmartsev, S.; Sotomayor, E.; Padhya, T.; McCaffrey, T.V.; McCaffrey, J.C.; Gabrilovich, D.I. Mechanism regulating reactive oxygen species in tumor-induced myeloid-derived suppressor cells. J. Immunol. 2009, 182, 5693–5701. [Google Scholar] [CrossRef]
  254. Erler, J.T.; Cawthorne, C.; Williams, K.J.; Koritzinsky, M.; Wouters, B.G.; Wilson, C.; Miller, C.J.; Demonacos, C.; Stratford, I.J.; Dive, C. Hypoxia-Mediated Down-Regulation of Bid and Bax in Tumors Occurs via Hypoxia-Inducible Factor 1-Dependent and -Independent Mechanisms and Contributes to Drug Resistance. Mol. Cell. Boil. 2004, 24, 2875–2889. [Google Scholar] [CrossRef] [Green Version]
  255. Sermeus, A.; Genin, M.; Maincent, A.; Fransolet, M.; Notte, A.; LeClere, L.; Riquier, H.; Arnould, T.; Michiels, C. Hypoxia-Induced Modulation of Apoptosis and BCL-2 Family Proteins in Different Cancer Cell Types. PLoS ONE 2012, 7, e47519. [Google Scholar] [CrossRef] [Green Version]
  256. Park, S.-Y.; Billiar, T.R.; Seol, D.-W. Hypoxia Inhibition of Apoptosis Induced by Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL). Biochem. Biophys. Res. Commun. 2002, 291, 150–153. [Google Scholar] [CrossRef]
  257. Piret, J.-P.; Minet, E.; Ninane, N.; Debacq, C.; Raes, M.; Cosse, J.-P.; Michiels, C. Hypoxia-inducible Factor-1-dependent Overexpression of Myeloid Cell Factor-1 Protects Hypoxic Cells against tert-Butyl Hydroperoxide-induced Apoptosis. J. Boil. Chem. 2004, 280, 9336–9344. [Google Scholar] [CrossRef] [Green Version]
  258. Koundouros, N.; Poulogiannis, G. Phosphoinositide 3-Kinase/Akt Signaling and Redox Metabolism in Cancer. Front. Oncol. 2018, 8, 160. [Google Scholar] [CrossRef]
  259. Chang, F.; Lee, J.T.; Navolanic, P.M.; Steelman, L.S.; Shelton, J.G.; Blalock, W.L.; Franklin, R.A.; McCubrey, J. Involvement of PI3K/Akt pathway in cell cycle progression, apoptosis, and neoplastic transformation: A Target for cancer chemotherapy. Leukemia 2003, 17, 590–603. [Google Scholar] [CrossRef] [Green Version]
  260. Sahai, E.; Astsaturov, I.; Cukierman, E.; DeNardo, D.G.; Egeblad, M.; Evans, R.M.; Fearon, D.; Greten, F.R.; Hingorani, S.R.; Hunter, T.; et al. A framework for advancing our understanding of cancer-associated fibroblasts. Nat. Rev. Cancer 2020, 20, 174–186. [Google Scholar] [CrossRef] [Green Version]
  261. Zhang, R.; Qi, F.; Zhao, F.; Li, G.; Shao, S.; Zhang, X.; Yuan, L.; Feng, Y. Cancer-associated fibroblasts enhance tumor-associated macrophages enrichment and suppress NK cells function in colorectal cancer. Cell Death Dis. 2019, 10, 273. [Google Scholar] [CrossRef] [Green Version]
  262. Ziani, L.; Ben Safta-Saadoun, T.; Gourbeix, J.; Cavalcanti, A.; Robert, C.; Favre, G.; Chouaib, S.; Thiery, J. Melanoma-associated fibroblasts decrease tumor cell susceptibility to NK cell-mediated killing through matrix-metalloproteinases secretion. Oncotarget 2017, 8, 19780–19794. [Google Scholar] [CrossRef] [Green Version]
  263. Takahashi, H.; Sakakura, K.; Kudo, T.; Toyoda, M.; Kaira, K.; Oyama, T.; Chikamatsu, K. Cancer-associated fibroblasts promote an immunosuppressive microenvironment through the induction and accumulation of protumoral macrophages. Oncotarget 2016, 8, 8633–8647. [Google Scholar] [CrossRef] [Green Version]
  264. Cheng, J.-T.; Deng, Y.-N.; Yi, H.-M.; Wang, G.-Y.; Fu, B.-S.; Chen, W.-J.; Liu, W.; Tai, Y.; Peng, Y.-W.; Zhang, Q. Hepatic carcinoma-associated fibroblasts induce IDO-producing regulatory dendritic cells through IL-6-mediated STAT3 activation. Oncogenesis 2016, 5, e198. [Google Scholar] [CrossRef] [Green Version]
  265. Ziani, L.; Chouaib, S.; Thiery, J. Alteration of the Antitumor Immune Response by Cancer-Associated Fibroblasts. Front. Immunol. 2018, 9, 414. [Google Scholar] [CrossRef]
  266. Pietra, G.; Manzini, C.; Rivara, S.; Vitale, M.; Cantoni, C.; Petretto, A.; Balsamo, M.; Conte, R.; Benelli, R.; Minghelli, S.; et al. Melanoma Cells Inhibit Natural Killer Cell Function by Modulating the Expression of Activating Receptors and Cytolytic Activity. Cancer Res. 2012, 72, 1407–1415. [Google Scholar] [CrossRef] [Green Version]
  267. Park, A.; Lee, Y.; Kim, M.S.; Kang, Y.J.; Park, Y.-J.; Jung, H.; Kim, T.-D.; Lee, H.G.; Choi, I.; Yoon, S.R. Prostaglandin E2 Secreted by Thyroid Cancer Cells Contributes to Immune Escape Through the Suppression of Natural Killer (NK) Cell Cytotoxicity and NK Cell Differentiation. Front. Immunol. 2018, 9. [Google Scholar] [CrossRef]
  268. Galland, S.; Vuille, J.; Martin, P.; Letovanec, I.; Caignard, A.; Fregni, G.; Stamenkovic, I. Tumor-Derived Mesenchymal Stem Cells Use Distinct Mechanisms to Block the Activity of Natural Killer Cell Subsets. Cell Rep. 2017, 20, 2891–2905. [Google Scholar] [CrossRef] [Green Version]
  269. Spaggiari, G.M.; Capobianco, A.; Abdelrazik, H.; Becchetti, F.; Mingari, M.C.; Moretta, L. Mesenchymal stem cells inhibit natural killer–cell proliferation, cytotoxicity, and cytokine production: Role of indoleamine 2,3-dioxygenase and prostaglandin E2. Blood 2008, 111, 1327–1333. [Google Scholar] [CrossRef]
Ijms 21 03726 g001 550
Figure 1. Effector mechanisms and tumor cell-resistance in NK cell-mediated apoptosis. NK cells eliminate target cells through death receptor-ligand engagement and the release of their cytotoxic granules containing granzymes and perforin. Nonetheless, genetic alterations, overexpression of anti-apoptotic proteins and the production of soluble decoy receptors represent critical factors affecting NK cell-mediated cytotoxicity.
Figure 1. Effector mechanisms and tumor cell-resistance in NK cell-mediated apoptosis. NK cells eliminate target cells through death receptor-ligand engagement and the release of their cytotoxic granules containing granzymes and perforin. Nonetheless, genetic alterations, overexpression of anti-apoptotic proteins and the production of soluble decoy receptors represent critical factors affecting NK cell-mediated cytotoxicity.
Ijms 21 03726 g001
Table
Table 1. Death receptors and ligands.
Table 1. Death receptors and ligands.
Receptor NameAlternative NameLigandsDeath Domains
TNF-R1P55/P60TNF-αY
FasCD95/APO-1FasL (CD95L)Y
TRAIL-R1DR4TRAILY
TRAIL-R2DR5TRAILY
TRAIL-R3DcR1TRAILN
TRAIL-R4DcR2TRAILN
OsteoprotegerinOPGTRAILN
EDAREctodysplasin-A receptorEctodysplasin A (EDA)N
NGFRP75(NTR)NGF, BDNF, NTF3, NTF4Y
Y = yes; N = no.
Table
Table 2. Mechanisms of resistance to NK cell-mediated cytotoxicity.
Table 2. Mechanisms of resistance to NK cell-mediated cytotoxicity.
ProteinMechanism of ResistanceCancerReference
Caspase-3Gene mutations that interfere with caspase activityGastric carcinoma[63]
Vulvar squamous carcinoma[64]
Hepatocellular carcinoma[65]
Caspase-4Advanced gastric adenocarcinoma and colorectal cancer[66]
Caspase-5MM, NHL, NSCLC, hepatocellular, colorectal and gastric carcinomas[67]
Caspase-6GIST[68]
Caspase-7NSCLC, colorectal and gastric carcinomas[69]
Caspase-8Colorectal, esophageal and head and neck carcinomas[70]
Caspase-9Colorectal and gastric carcinomas[71]
SurvivinAberrant expression by chromosomal amplificationNeuroblastoma[72]
c-IAP1Esophageal, liver, lung and ovarian carcinomas[73,74]
c-IAP2Aberrant activity by chromosomal translocationMALT lymphomas[75]
BaxInactivating gene mutationsColon and gastric carcinomas with microsatellite instability[76,77,78]
T-ALL[79]
CLL[80]
Burkitt’s lymphoma[81]
BCL2Aberrant expression by chromosomal translocationDLBCL[82]
Homologue protein expression by cancer-associated virusesKaposi’s sarcoma[83]
c-FLIPHomologue protein expression by cancer-associated virusesKaposi’s sarcoma[84]
Aberrant protein expressionBurkitt’s lymphoma[85]
AML[86]
Colorectal cancer[87]
BimGene deletionMCL[88,89]
NoxaSilencing gene mutationsDLBCL[89]
TRAIL-R1Gene mutations that interfere with receptor activityLung, head and neck and gastric carcinomas[90]
NHL[91]
Allelic deletionB-NHL[92]
Breast cancer[93]
TRAIL-R2Allelic deletionB-NHL[92]
Breast cancer[93]
Loss-of-function mutationsHead and neck and lung carcinomas[94]
NSCLC[95]
Gastric cancer[96]
Gene mutations that interfere with receptor activityNHL[91]
FasLoss-of-function mutationsHematological malignancies[97]
OsteoprotegerinAberrant protein expressionMM[98]
DcR3Glioblastoma[99]
Breast cancer[100]
Gastric cancer[101]
Colorectal cancer[102]
TRAIL-R3AML[103]
Breast cancer[104]
TRAIL-R4Prostate cancer[105]
PRF1Downregulation of protein expressionPancreatic, gastric and colorectal carcinomas[106]
Lung cancer[107]
Hepatocellular carcinoma[108]
Reduction of protein levels by tumor-associated cellsT-cell lymphoma[109]
Hepatocellular carcinoma[110]
Melanoma[111]
Colorectal cancer[112]
Impaired cell surface bindingAML[113]
Impaired protein mobilization to the immune synapseBurkitt’s lymphoma[114]
GMZBDownregulation of protein expressionLung cancer[115]
Hepatocellular carcinoma[108]
Lung cancer[107]
Increased protein degradationBreast cancer[116,117]
Serpin B9Aberrant protein expressionDLBCL[118]
NSCLC[119]
Lung cancer[120]
Serpin B4Squamous cell carcinomas[121,122,123]
CD107aDownregulation of protein expressionPancreatic cancer[124]
F-actinIntracellular accumulationBreast cancer[125]
Connexin-43Increased protein degradationMelanoma[126]
NSCLC = non-small cell lung cancer, GIST = gastrointestinal stromal tumor, MALT = mucosa-associated lymphoid tissue, CLL = chronic lymphocytic leukemia, ALL = acute lymphoid leukemia, DLBCL = diffuse large B-cell lymphoma, AML = acute myeloid leukemia, MCL = mantle cell lymphoma, MM = Multiple myeloma, NHL = non-Hodgkin lymphoma.

Share and Cite

MDPI and ACS Style

Sordo-Bahamonde, C.; Lorenzo-Herrero, S.; Payer, Á.R.; Gonzalez, S.; López-Soto, A. Mechanisms of Apoptosis Resistance to NK Cell-Mediated Cytotoxicity in Cancer. Int. J. Mol. Sci. 2020, 21, 3726. https://doi.org/10.3390/ijms21103726

AMA Style

Sordo-Bahamonde C, Lorenzo-Herrero S, Payer ÁR, Gonzalez S, López-Soto A. Mechanisms of Apoptosis Resistance to NK Cell-Mediated Cytotoxicity in Cancer. International Journal of Molecular Sciences. 2020; 21(10):3726. https://doi.org/10.3390/ijms21103726

Chicago/Turabian Style

Sordo-Bahamonde, Christian, Seila Lorenzo-Herrero, Ángel R. Payer, Segundo Gonzalez, and Alejandro López-Soto. 2020. "Mechanisms of Apoptosis Resistance to NK Cell-Mediated Cytotoxicity in Cancer" International Journal of Molecular Sciences 21, no. 10: 3726. https://doi.org/10.3390/ijms21103726

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop