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Natural Killer Cells and Cancer Therapy
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Natural Killer Cells and Cancer Therapy

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (15 November 2018) | Viewed by 103223

Special Issue Editors

Dr. Thierry Walzer

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Guest Editor
Centre International de Recherche en Infectiologie, Lyon, France
Interests: Natural Killer cells; immunotherapy; signal transduction; cell migration; lymphocyte reactivity
Dr. Sebastien Viel

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Guest Editor
Centre International de Recherche en Infectiologie, Lyon, France; Laboratoire d’Immunologie, Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, 69310 Pierre-Bénite, France
Dr. Antoine Marçais

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Guest Editor
Centre International de Recherche en Infectiologie, Lyon, France

Special Issue Information

Dear Colleagues,

Immunotherapy is rapidly developing for many cancers and will certainly become the mainstay of treatment under various conditions. Current immunotherapies target T cells and are designed to promote or restore their activities by blocking immune checkpoints (ICP), such as PD-1. Yet, other effector cells, such as Natural Killer (NK) cell, are endowed with a strong and specific anti-tumor potential that could be harnessed, with perhaps less collateral damage (auto-immunity or immunopathology). NK cells express dedicated receptors that allow them to recognize a broad range of tumor cells of various origins. Upon activation, they can kill target cells and release IFNg and other factors that contribute to tumor elimination and control of metastatic dissemination. NK cell-based therapies are under investigation in patients and include for example antibodies blocking inhibitory NK cell receptors, bispecific antibodies triggering NK cell activation, cytokines boosting NK cell cytotoxic potential, or infusions of in vitro activated NK cells expressing or not chimeric-antigen receptors. Such strategies could be combined to more conventional therapies (chemotherapies, radiotherapy, etc.) to increase their success rate. Enhancement of NK cell activity is especially needed in cases of tumor relapse after ICP blockade, a situation often associated with the loss of MHC-I expression. As NK cells are sensitive to exhaustion strategies to avoid or reverse NK cell exhaustion should also be designed. This series of articles reviews the current literature on NK cells and cancer therapy, from basic conceptual aspects to clinical applications.

Dr. Thierry Walzer
Dr. Sebastien Viel
Dr. Antoine Marçais
Guest Editors

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Published Papers (15 papers)

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Research

Jump to: Review

13 pages, 684 KiB  
Article
NKG2D Polymorphism in Melanoma Patients from Southeastern Spain
by Lourdes Gimeno, Helios Martínez-Banaclocha, M. Victoria Bernardo, José Miguel Bolarin, Luis Marín, Ruth López-Hernández, M. Rocío López-Alvarez, M. Rosa Moya-Quiles, Manuel Muro, José Francisco Frias-Iniesta, Jorge Martínez-Escribano, M. Rocío Alvarez-López, Alfredo Minguela and José Antonio Campillo
Cancers 2019, 11(4), 438; https://doi.org/10.3390/cancers11040438 - 28 Mar 2019
Cited by 6 | Viewed by 3114
Abstract
Background: Natural killer (NK) and CD8+ T cells are involved in the immune response against melanoma. C-Type lectin-like NK cell receptors are located in the Natural Killer Complex (NKC) region 12p13.2-p12.3 and play a critical role in regulating the activity of NK and [...] Read more.
Background: Natural killer (NK) and CD8+ T cells are involved in the immune response against melanoma. C-Type lectin-like NK cell receptors are located in the Natural Killer Complex (NKC) region 12p13.2-p12.3 and play a critical role in regulating the activity of NK and CD8+ T cells. An association between polymorphisms in the NKC region, including the NKG2D gene and NKG2A promoter, and the risk of cancer has been previously described. The aim of this study was to analyze the association of polymorphisms in the NKC region with cutaneous melanoma in patients from southeastern Spain. Methods: Seven single-nucleotide polymorphisms (SNPs) in the NKG2D gene (NKC3,4,7,9,10,11,12), and one SNP in the NKG2A promoter (NKC17) were genotyped by a TaqMan 5′ Nuclease Assay in 233 melanoma patients and 200 matched healthy controls. Results: A linkage disequilibrium analysis of the SNPs performed in the NKC region revealed two blocks of haplotypes (Hb-1 and Hb-2) with 14 and seven different haplotype subtypes, respectively. The third most frequent haplotype from the block Hb-2—NK3 (CAT haplotype)—was significantly more frequent on melanoma patients than on healthy controls (p = 0.00009, Pc = 0.0006). No further associations were found when NKC SNPs were considered independently. Conclusions: Our results suggest an association between NKG2D polymorphisms and the risk of cutaneous malignant melanoma. Full article
(This article belongs to the Special Issue Natural Killer Cells and Cancer Therapy)
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20 pages, 3680 KiB  
Article
Bortezomib Augments Natural Killer Cell Targeting of Stem-Like Tumor Cells
by Jesus I. Luna, Steven K. Grossenbacher, Ian R. Sturgill, Erik Ames, Sean J. Judge, Lyes A. Bouzid, Morgan A. Darrow, William J. Murphy and Robert J. Canter
Cancers 2019, 11(1), 85; https://doi.org/10.3390/cancers11010085 - 14 Jan 2019
Cited by 21 | Viewed by 4282
Abstract
Tumor cells harboring stem-like/cancer stem cell (CSC) properties have been identified and isolated from numerous hematological and solid malignancies. These stem-like tumor cells can persist following conventional cytoreductive therapies, such as chemotherapy and radiotherapy, thereby repopulating the tumor and seeding relapse and/or metastasis. [...] Read more.
Tumor cells harboring stem-like/cancer stem cell (CSC) properties have been identified and isolated from numerous hematological and solid malignancies. These stem-like tumor cells can persist following conventional cytoreductive therapies, such as chemotherapy and radiotherapy, thereby repopulating the tumor and seeding relapse and/or metastasis. We have previously shown that natural killer (NK) cells preferentially target stem-like tumor cells via non- major histocompatibility complex (MHC) restricted mechanisms. Here, we demonstrated that the proteasome inhibitor, bortezomib, augments NK cell targeting of stem cell-like tumor cells against multiple solid human tumor-derived cancer lines and primary tissue samples. Mechanistically, this was mediated by the upregulation of cell surface NK ligands MHC class I chain-related protein A and B (MICA and MICB) on aldehyde dehydrogenases (ALDH)-positive CSCs. The increased expression of MICA and MICB on CSC targets thereby enhanced NK cell mediated killing in vitro and ex vivo from both human primary tumor and patient-derived xenograft samples. In vivo, the combination of bortezomib and allogeneic NK cell adoptive transfer in immunodeficient mice led to increased elimination of CSCs as well as tumor growth delay of orthotopic glioblastoma tumors. Taken together, our data support the combination bortezomib and NK transfer as a strategy for both CSC targeting and potentially improved outcomes in clinical cancer patients. Full article
(This article belongs to the Special Issue Natural Killer Cells and Cancer Therapy)
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15 pages, 2203 KiB  
Article
Novel Immunoregulatory Functions of IL-18, an Accomplice of TGF-β1
by Beatrice Casu, Alessandra Dondero, Stefano Regis, Fabio Caliendo, Andrea Petretto, Martina Bartolucci, Francesca Bellora, Cristina Bottino and Roberta Castriconi
Cancers 2019, 11(1), 75; https://doi.org/10.3390/cancers11010075 - 11 Jan 2019
Cited by 16 | Viewed by 3210
Abstract
TGF-β1 is a pleiotropic factor exerting a strong regulatory role in several cell types, including immune cells. In NK cells it profoundly alters the surface expression of crucial activating and chemokine receptors. To understand which soluble signals might better contrast these effects, we [...] Read more.
TGF-β1 is a pleiotropic factor exerting a strong regulatory role in several cell types, including immune cells. In NK cells it profoundly alters the surface expression of crucial activating and chemokine receptors. To understand which soluble signals might better contrast these effects, we cultured human NK cells in the presence of TGF-β1 and different innate and adaptive cytokines, generally referred as “immunostimulatory”. These included IL-2, IL-15, IL-21, IL-27, and IL-18. Unexpectedly, IL-18 strengthened rather than contrasting important TGF-β1-mediated functions. In particular, IL-18 further reduced the expression of CX3CR1 and NKp30, leading to the virtual abrogation of the triggering capability of this activating receptor. Moreover, IL-18 further increased the expression of CXCR4. The IL-18-mediated additive effect on NKp30 and CXCR4 expression involved transcriptional regulation and activation of MEK/ERK and/or p38MAPK. A proteomic approach quantified both surface and intracellular proteins significantly modified in cytokine-treated NK cells, thus giving global information on the biological processes involving TGF-β1 and IL-18. Our data support the concept that IL-18 may have a different behavior depending on the type of soluble factors characterizing the microenvironment. In a TGF-β1 rich milieu such as tumors, it may contribute to the impairment of both NK cells recruitment and killing capability. Full article
(This article belongs to the Special Issue Natural Killer Cells and Cancer Therapy)
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16 pages, 3355 KiB  
Article
Functional Assessment for Clinical Use of Serum-Free Adapted NK-92 Cells
by Michael Chrobok, Carin I. M. Dahlberg, Ece Canan Sayitoglu, Vladimir Beljanski, Hareth Nahi, Mari Gilljam, Birgitta Stellan, Tolga Sutlu, Adil Doganay Duru and Evren Alici
Cancers 2019, 11(1), 69; https://doi.org/10.3390/cancers11010069 - 10 Jan 2019
Cited by 19 | Viewed by 6910
Abstract
Natural killer (NK) cells stand out as promising candidates for cellular immunotherapy due to their capacity to kill malignant cells. However, the therapeutic use of NK cells is often dependent on cell expansion and activation with considerable amounts of serum and exogenous cytokines. [...] Read more.
Natural killer (NK) cells stand out as promising candidates for cellular immunotherapy due to their capacity to kill malignant cells. However, the therapeutic use of NK cells is often dependent on cell expansion and activation with considerable amounts of serum and exogenous cytokines. We aimed to develop an expansion protocol for NK-92 cells in an effort to generate a cost-efficient, xeno-free, clinical grade manufactured master cell line for therapeutic applications. By making functional assays with NK-92 cells cultured under serum-free conditions (NK-92SF) and comparing to serum-supplemented NK-92 cells (NK-92S) we did not observe significant alterations in the viability, proliferation, receptor expression levels, or in perforin and granzyme levels. Interestingly, even though NK-92SF cells displayed decreased degranulation and cytotoxicity against tumor cells in vitro, the degranulation capacity was recovered after overnight incubation with 20% serum in the medium. Moreover, lentiviral vector-based genetic modification efficiency of NK-92SF cells was comparable with NK-92S cells. The application of similar strategies can be useful in reducing the costs of manufacturing cells for clinical use and can help us understand and implement strategies towards chemically defined expansion and genetic modification protocols. Full article
(This article belongs to the Special Issue Natural Killer Cells and Cancer Therapy)
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11 pages, 1986 KiB  
Article
Key Role of the CD56lowCD16low Natural Killer Cell Subset in the Recognition and Killing of Multiple Myeloma Cells
by Elisabetta Vulpis, Helena Stabile, Alessandra Soriani, Cinzia Fionda, Maria Teresa Petrucci, Elena Mariggio’, Maria Rosaria Ricciardi, Marco Cippitelli, Angela Gismondi, Angela Santoni and Alessandra Zingoni
Cancers 2018, 10(12), 473; https://doi.org/10.3390/cancers10120473 - 29 Nov 2018
Cited by 27 | Viewed by 4239
Abstract
Natural Killer (NK) cells play a pivotal role in the immunosurveillance of Multiple Myeloma (MM), but it is still undefined whether the NK cell functional properties underlying their protective activity against MM are confined to distinct NK cell populations. Interestingly, herein we report [...] Read more.
Natural Killer (NK) cells play a pivotal role in the immunosurveillance of Multiple Myeloma (MM), but it is still undefined whether the NK cell functional properties underlying their protective activity against MM are confined to distinct NK cell populations. Interestingly, herein we report that the CD56lowCD16low NK cell subset displayed higher cytolytic activity compared to the other NK cell subsets (i.e., CD56highCD16+/−, CD56lowCD16high) against MM cells and its activity was impaired in MM patients. Decreased DNAM-1 expression levels were observed on the CD56lowCD16low NK cells during MM progression. Evaluating NK cell subset frequency after autologous hematopoietic stem cell transplantation, we found that CD56lowCD16low NK cells recovered earlier after transplantation. Overall, our data denote a key role of CD56lowCD16low subpopulation in the killing of MM cells and suggest that the reconstitution of CD56lowCD16low subpopulation after HSCT could be a useful approach of adoptive immunotherapy in the treatment of relapsed/refractory MM patients. Full article
(This article belongs to the Special Issue Natural Killer Cells and Cancer Therapy)
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19 pages, 2221 KiB  
Article
TGFβ Imprinting During Activation Promotes Natural Killer Cell Cytokine Hypersecretion
by Jennifer A. Foltz, Jena E. Moseman, Aarohi Thakkar, Nitin Chakravarti and Dean A. Lee
Cancers 2018, 10(11), 423; https://doi.org/10.3390/cancers10110423 - 05 Nov 2018
Cited by 35 | Viewed by 5011
Abstract
Transforming growth factor-beta (TGFβ) is a potent immunosuppressive cytokine that inhibits the anti-tumor responses of NK cells and T cells. However, the stimulation of natural killer (NK) cells with pro-inflammatory cytokines decreases NK cell sensitivity to TGFβ. Herein, we sought to determine if [...] Read more.
Transforming growth factor-beta (TGFβ) is a potent immunosuppressive cytokine that inhibits the anti-tumor responses of NK cells and T cells. However, the stimulation of natural killer (NK) cells with pro-inflammatory cytokines decreases NK cell sensitivity to TGFβ. Herein, we sought to determine if TGFβ imprinting (TGFβi) during NK cell activation and expansion would decrease NK cell sensitivity to TGFβ suppression. To this end, we demonstrate that the activation of NK cells during chronic IL-2 stimulation and TGFβi potently induces NK cell hypersecretion of interferon-gamma (IFNγ) and tumor necrosis factor-alpha (TNFα) in response to tumor targets which persists for at least one month in vitro after the removal of TGFβ. TGFβi NK cell cytokine hypersecretion is induced following both cytokine and tumor activation. Further, TGFβi NK cells have a marked suppression of SMAD3 and T-bet which is associated with altered chromatin accessibility. In contrast to their heightened cytokine secretion, TGFβi NK cells downregulate several activating receptors, granzyme and perforin, and upregulate TRAIL, leading to cell-line-specific alterations in cytotoxicity. These findings may impact our understanding of how TGFβ affects NK cell development and anti-tumor function. Full article
(This article belongs to the Special Issue Natural Killer Cells and Cancer Therapy)
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Review

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21 pages, 532 KiB  
Review
State of the Art of Natural Killer Cell Imaging: A Systematic Review
by Michela Varani, Sveva Auletta, Alberto Signore and Filippo Galli
Cancers 2019, 11(7), 967; https://doi.org/10.3390/cancers11070967 - 09 Jul 2019
Cited by 11 | Viewed by 3312
Abstract
Natural killer (NK) cell therapy is a promising alternative to conventional T cell-based treatments, although there is a lack of diagnostic tools to predict and evaluate therapeutic outcomes. Molecular imaging can offer several approaches to non-invasively address this issue. In this study, we [...] Read more.
Natural killer (NK) cell therapy is a promising alternative to conventional T cell-based treatments, although there is a lack of diagnostic tools to predict and evaluate therapeutic outcomes. Molecular imaging can offer several approaches to non-invasively address this issue. In this study, we systematically reviewed the literature to evaluate the state of the art of NK cell imaging and its translational potential. PubMed and Scopus databases were searched for published articles on the imaging of NK cells in humans and preclinical models. Study quality was evaluated following Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) criteria. We pooled studies as follows: Optical, magnetic resonance imaging (MRI) and nuclear medicine imaging with a total of 21 studies (n = 5, n = 8 and n = 8, respectively). Considering the limitation of comparing different imaging modalities, it appears that optical imaging (OI) of NK cells is very useful in a preclinical setting, but has the least translational potential. MRI provides high quality images without ionizing radiations with lower sensitivity. Nuclear medicine is the only imaging technique that has been applied in humans (four papers), but results were not outstanding due to a limited number of enrolled patients. At present, no technique emerged as superior over the others and more standardization is required in conducting human and animal studies. Full article
(This article belongs to the Special Issue Natural Killer Cells and Cancer Therapy)
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15 pages, 1218 KiB  
Review
DNAM-1 and the TIGIT/PVRIG/TACTILE Axis: Novel Immune Checkpoints for Natural Killer Cell-Based Cancer Immunotherapy
by Beatriz Sanchez-Correa, Isabel Valhondo, Fakhri Hassouneh, Nelson Lopez-Sejas, Alejandra Pera, Juan M. Bergua, Maria Jose Arcos, Helena Bañas, Ignacio Casas-Avilés, Esther Durán, Corona Alonso, Rafael Solana and Raquel Tarazona
Cancers 2019, 11(6), 877; https://doi.org/10.3390/cancers11060877 - 23 Jun 2019
Cited by 144 | Viewed by 13575
Abstract
Natural killer (NK) cells are lymphocytes of the innate immune response characterized by their role in the destruction of tumor cells. Activation of NK cells depend on a fine balance between activating and inhibitory signals mediated by different receptors. In recent years, a [...] Read more.
Natural killer (NK) cells are lymphocytes of the innate immune response characterized by their role in the destruction of tumor cells. Activation of NK cells depend on a fine balance between activating and inhibitory signals mediated by different receptors. In recent years, a family of paired receptors that interact with ligands of the Nectin/Nectin-like (Necl) family has attracted great interest. Two of these ligands, Necl-5 (usually termed CD155 or PVR) and Nectin-2 (CD112), frequently expressed on different types of tumor cells, are recognized by a group of receptors expressed on T and NK cells that exert opposite functions after interacting with their ligands. These receptors include DNAM-1 (CD226), TIGIT, TACTILE (CD96) and the recently described PVRIG. Whereas activation through DNAM-1 after recognition of CD155 or CD112 enhances NK cell-mediated cytotoxicity against a wide range of tumor cells, TIGIT recognition of these ligands exerts an inhibitory effect on NK cells by diminishing IFN-γ production, as well as NK cell-mediated cytotoxicity. PVRIG has also been identified as an inhibitory receptor that recognizes CD112 but not CD155. However, little is known about the role of TACTILE as modulator of immune responses in humans. TACTILE control of tumor growth and metastases has been reported in murine models, and it has been suggested that it negatively regulates the anti-tumor functions mediated by DNAM-1. In NK cells from patients with solid cancer and leukemia, it has been observed a decreased expression of DNAM-1 that may shift the balance in favor to the inhibitory receptors TIGIT or PVRIG, further contributing to the diminished NK cell-mediated cytotoxic capacity observed in these patients. Analysis of DNAM-1, TIGIT, TACTILE and PVRIG on human NK cells from solid cancer or leukemia patients will clarify the role of these receptors in cancer surveillance. Overall, it can be speculated that in cancer patients the TIGIT/PVRIG pathways are upregulated and represent novel targets for checkpoint blockade immunotherapy. Full article
(This article belongs to the Special Issue Natural Killer Cells and Cancer Therapy)
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12 pages, 1206 KiB  
Review
Dysregulation of Natural Killer Cells in Obesity
by Donal O’Shea and Andrew E. Hogan
Cancers 2019, 11(4), 573; https://doi.org/10.3390/cancers11040573 - 23 Apr 2019
Cited by 74 | Viewed by 10145
Abstract
Natural killer (NK) cells are a population of lymphocytes which classically form part of the innate immune system. They are defined as innate lymphocytes, due to their ability to kill infected or transformed cells without prior activation. In addition to their cytotoxic abilities, [...] Read more.
Natural killer (NK) cells are a population of lymphocytes which classically form part of the innate immune system. They are defined as innate lymphocytes, due to their ability to kill infected or transformed cells without prior activation. In addition to their cytotoxic abilities, NK cells are also rapid producers of inflammatory cytokines such as interferon gamma (IFN-γ) and are therefore a critical component of early immune responses. Due to these unique abilities, NK cells are a very important component of host protection, especially anti-tumour and anti-viral immunity. Obesity is a worldwide epidemic, with over 600 million adults and 124 million children now classified as obese. It is well established that individuals who are obese are at a higher risk of many acute and chronic conditions, including cancer and viral infections. Over the past 10 years, many studies have investigated the impact of obesity on NK cell biology, detailing systemic dysregulation of NK cell functions. More recently, several studies have investigated the role of NK cells in the homeostasis of adipose tissue and the pathophysiology of obesity. In this review, we will discuss in detail these studies and focus on emerging data detailing the metabolic mechanisms altering NK cells in obesity. Full article
(This article belongs to the Special Issue Natural Killer Cells and Cancer Therapy)
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29 pages, 1552 KiB  
Review
Natural Killer Cells as Key Players of Tumor Progression and Angiogenesis: Old and Novel Tools to Divert Their Pro-Tumor Activities into Potent Anti-Tumor Effects
by Barbara Bassani, Denisa Baci, Matteo Gallazzi, Alessandro Poggi, Antonino Bruno and Lorenzo Mortara
Cancers 2019, 11(4), 461; https://doi.org/10.3390/cancers11040461 - 01 Apr 2019
Cited by 112 | Viewed by 10311
Abstract
Immune cells, as a consequence of their plasticity, can acquire altered phenotype/functions within the tumor microenvironment (TME). Some of these aberrant functions include attenuation of targeting and killing of tumor cells, tolerogenic/immunosuppressive behavior and acquisition of pro-angiogenic activities. Natural killer (NK) cells are [...] Read more.
Immune cells, as a consequence of their plasticity, can acquire altered phenotype/functions within the tumor microenvironment (TME). Some of these aberrant functions include attenuation of targeting and killing of tumor cells, tolerogenic/immunosuppressive behavior and acquisition of pro-angiogenic activities. Natural killer (NK) cells are effector lymphocytes involved in tumor immunosurveillance. In solid malignancies, tumor-associated NK cells (TANK cells) in peripheral blood and tumor-infiltrating NK (TINK) cells show altered phenotypes and are characterized by either anergy or reduced cytotoxicity. Here, we aim at discussing how NK cells can support tumor progression and how induction of angiogenesis, due to TME stimuli, can be a relevant part on the NK cell-associated tumor supporting activities. We will review and discuss the contribution of the TME in shaping NK cell response favoring cancer progression. We will focus on TME-derived set of factors such as TGF-β, soluble HLA-G, prostaglandin E2, adenosine, extracellular vesicles, and miRNAs, which can exhibit a dual function. On one hand, these factors can suppress NK cell-mediated activities but, on the other hand, they can induce a pro-angiogenic polarization in NK cells. Also, we will analyze the impact on cancer progression of the interaction of NK cells with several TME-associated cells, including macrophages, neutrophils, mast cells, cancer-associated fibroblasts, and endothelial cells. Then, we will discuss the most relevant therapeutic approaches aimed at potentiating/restoring NK cell activities against tumors. Finally, supported by the literature revision and our new findings on NK cell pro-angiogenic activities, we uphold NK cells to a key host cellular paradigm in controlling tumor progression and angiogenesis; thus, we should bear in mind NK cells like a TME-associated target for anti-tumor therapeutic approaches. Full article
(This article belongs to the Special Issue Natural Killer Cells and Cancer Therapy)
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15 pages, 825 KiB  
Review
Size Matters: The Functional Role of the CEACAM1 Isoform Signature and Its Impact for NK Cell-Mediated Killing in Melanoma
by Iris Helfrich and Bernhard B. Singer
Cancers 2019, 11(3), 356; https://doi.org/10.3390/cancers11030356 - 13 Mar 2019
Cited by 30 | Viewed by 5396
Abstract
Malignant melanoma is the most aggressive and treatment resistant type of skin cancer. It is characterized by continuously rising incidence and high mortality rate due to its high metastatic potential. Various types of cell adhesion molecules have been implicated in tumor progression in [...] Read more.
Malignant melanoma is the most aggressive and treatment resistant type of skin cancer. It is characterized by continuously rising incidence and high mortality rate due to its high metastatic potential. Various types of cell adhesion molecules have been implicated in tumor progression in melanoma. One of these, the carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), is a multi-functional receptor protein potentially expressed in epithelia, endothelia, and leukocytes. CEACAM1 often appears in four isoforms differing in the length of their extracellular and intracellular domains. Both the CEACAM1 expression in general, and the ratio of the expressed CEACAM1 splice variants appear very dynamic. They depend on both the cell activation stage and the cell growth phase. Interestingly, normal melanocytes are negative for CEACAM1, while melanomas often show high expression. As a cell–cell communication molecule, CEACAM1 mediates the direct interaction between tumor and immune cells. In the tumor cell this interaction leads to functional inhibitions, and indirectly to decreased cancer cell immunogenicity by down-regulation of ligands of the NKG2D receptor. On natural killer (NK) cells it inhibits NKG2D-mediated cytolysis and signaling. This review focuses on novel mechanistic insights into CEACAM1 isoforms for NK cell-mediated immune escape mechanisms in melanoma, and their clinical relevance in patients suffering from malignant melanoma. Full article
(This article belongs to the Special Issue Natural Killer Cells and Cancer Therapy)
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21 pages, 563 KiB  
Review
Exploiting NK Cell Surveillance Pathways for Cancer Therapy
by Alexander David Barrow and Marco Colonna
Cancers 2019, 11(1), 55; https://doi.org/10.3390/cancers11010055 - 08 Jan 2019
Cited by 37 | Viewed by 7564
Abstract
Natural killer (NK) cells can evoke potent anti-tumour activity. This function is largely mediated through a battery of specialised cell-surface receptors which probe the tissue microenvironment for changes in surface and secretory phenotypes that may alert to the presence of infection or malignancy. [...] Read more.
Natural killer (NK) cells can evoke potent anti-tumour activity. This function is largely mediated through a battery of specialised cell-surface receptors which probe the tissue microenvironment for changes in surface and secretory phenotypes that may alert to the presence of infection or malignancy. These receptors have the potential to arouse the robust cytotoxic and cytokine-secreting functions of NK cells and so must be tightly regulated to prevent autoimmunity. However, such functions also hold great promise for clinical intervention. In this review, we highlight some of the latest breakthroughs in fundamental NK cell receptor biology that have illuminated our understanding of the molecular strategies NK cells employ to perceive malignant cells from normal healthy cells. Moreover, we highlight how these sophisticated tumour recognition strategies are being harnessed for cancer immunotherapies in the clinic. Full article
(This article belongs to the Special Issue Natural Killer Cells and Cancer Therapy)
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22 pages, 655 KiB  
Review
NK Cell-Based Immunotherapy in Cancer Metastasis
by Seila Lorenzo-Herrero, Alejandro López-Soto, Christian Sordo-Bahamonde, Ana P Gonzalez-Rodriguez, Massimo Vitale and Segundo Gonzalez
Cancers 2019, 11(1), 29; https://doi.org/10.3390/cancers11010029 - 28 Dec 2018
Cited by 80 | Viewed by 11068
Abstract
Metastasis represents the leading cause of cancer-related death mainly owing to the limited efficacy of current anticancer therapies on advanced malignancies. Although immunotherapy is rendering promising results in the treatment of cancer, many adverse events and factors hampering therapeutic efficacy, especially in solid [...] Read more.
Metastasis represents the leading cause of cancer-related death mainly owing to the limited efficacy of current anticancer therapies on advanced malignancies. Although immunotherapy is rendering promising results in the treatment of cancer, many adverse events and factors hampering therapeutic efficacy, especially in solid tumors and metastases, still need to be solved. Moreover, immunotherapeutic strategies have mainly focused on modulating the activity of T cells, while Natural Killer (NK) cells have only recently been taken into consideration. NK cells represent an attractive target for cancer immunotherapy owing to their innate capacity to eliminate malignant tumors in a non-Major Histocompatibility Complex (MHC) and non-tumor antigen-restricted manner. In this review, we analyze the mechanisms and efficacy of NK cells in the control of metastasis and we detail the immunosubversive strategies developed by metastatic cells to evade NK cell-mediated immunosurveillance. We also share current and cutting-edge clinical approaches aimed at unleashing the full anti-metastatic potential of NK cells, including the adoptive transfer of NK cells, boosting of NK cell activity, redirecting NK cell activity against metastatic cells and the release of evasion mechanisms dampening NK cell immunosurveillance. Full article
(This article belongs to the Special Issue Natural Killer Cells and Cancer Therapy)
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23 pages, 1312 KiB  
Review
The Potential for Cancer Immunotherapy in Targeting Surgery-Induced Natural Killer Cell Dysfunction
by Marisa Market, Katherine E. Baxter, Leonard Angka, Michael A. Kennedy and Rebecca C. Auer
Cancers 2019, 11(1), 2; https://doi.org/10.3390/cancers11010002 - 20 Dec 2018
Cited by 19 | Viewed by 7700
Abstract
Natural Killer (NK) cells are granular lymphocytes of the innate immune system that are able to recognize and kill tumor cells without undergoing clonal selection. Discovered over 40 years ago, they have since been recognized to possess both cytotoxic and cytokine-producing effector functions. [...] Read more.
Natural Killer (NK) cells are granular lymphocytes of the innate immune system that are able to recognize and kill tumor cells without undergoing clonal selection. Discovered over 40 years ago, they have since been recognized to possess both cytotoxic and cytokine-producing effector functions. Following trauma, NK cells are suppressed and their effector functions are impaired. This is especially important for cancer patients undergoing the removal of solid tumors, as surgery has shown to contribute to the development of metastasis and cancer recurrence postoperatively. We have recently shown that NK cells are critical mediators in the formation of metastasis after surgery. While research into the mechanism(s) responsible for NK cell dysfunction is ongoing, knowledge of these mechanisms will pave the way for perioperative therapeutics with the potential to improve cancer outcomes by reversing NK cell dysfunction. This review will discuss mechanisms of suppression in the postoperative environment, including hypercoagulability, suppressive soluble factors, the expansion of suppressive cell populations, and how this affects NK cell biology, including modulation of cell surface receptors, the potential for anergy, and immunosuppressive NK cell functions. This review will also outline potential immunotherapies to reverse postoperative NK dysfunction, with the goal of preventing surgery-induced metastasis. Full article
(This article belongs to the Special Issue Natural Killer Cells and Cancer Therapy)
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16 pages, 1079 KiB  
Review
NK Cell-Based Glioblastoma Immunotherapy
by Irene Golán, Laura Rodríguez de la Fuente and Jose A. Costoya
Cancers 2018, 10(12), 522; https://doi.org/10.3390/cancers10120522 - 18 Dec 2018
Cited by 62 | Viewed by 6149
Abstract
Glioblastoma (GB) is the most aggressive and most common malignant primary brain tumor diagnosed in adults. GB shows a poor prognosis and, unfortunately, current therapies are unable to improve its clinical outcome, imposing the need for innovative therapeutic approaches. The main reason for [...] Read more.
Glioblastoma (GB) is the most aggressive and most common malignant primary brain tumor diagnosed in adults. GB shows a poor prognosis and, unfortunately, current therapies are unable to improve its clinical outcome, imposing the need for innovative therapeutic approaches. The main reason for the poor prognosis is the great cell heterogeneity of the tumor mass and its high capacity for invading healthy tissues. Moreover, the glioblastoma microenvironment is capable of suppressing the action of the immune system through several mechanisms such as recruitment of cell modulators. Development of new therapies that avoid this immune evasion could improve the response to the current treatments for this pathology. Natural Killer (NK) cells are cellular components of the immune system more difficult to deceive by tumor cells and with greater cytotoxic activity. Their use in immunotherapy gains strength because they are a less toxic alternative to existing therapy, but the current research focuses on mimicking the NK attack strategy. Here, we summarize the most recent studies regarding molecular mechanisms involved in the GB and immune cells interaction and highlight the relevance of NK cells in the new therapeutic challenges. Full article
(This article belongs to the Special Issue Natural Killer Cells and Cancer Therapy)
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