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Emerging Roles of Chemokines in Cancer Immunotherapy
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Emerging Roles of Chemokines in Cancer Immunotherapy

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Immunology and Immunotherapy".

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 67782

Special Issue Editor

Prof. Dr. Bernhard Moser

E-Mail Website
Guest Editor
Institute of Infection & Immunity, Cardiff University School of Medicine, Cardiff CF14 4XN, Wales, UK
Interests: Chemokines; T Cells; Immune system; Cancer immunotherapy; Signaling

Special Issue Information

Dear Colleagues,

Current cancer therapy is progressing with increasing speed thanks to the development of immune checkpoint-targeted therapies. The success of blocking antibodies specific for the inhibitory co-receptors CTLA-4 and PD-1/PD-L1 has unequivocally demonstrated the critical importance of the immune system in cancer control. Their use represents a game change in cancer therapy, especially when combined with standard therapies such as surgery, radiation, and chemotherapy. However, the majority of patients with solid cancer still do not benefit from immune checkpoint blockage (ICB) therapy. Clearly, other inhibitory mechanisms, in addition to CTLA-4 and PD-1/PD-L1, may prevent the induction of effective antitumour immune responses and full recovery.

The compartment of immune cells in the tumour microenvironment resembles chronically inflamed tissues and healing wounds and includes both resident and recruited immune cells. Unsurprisingly, chemokines are recognised as key regulators of cancers, as attested to by an avalanche of recent studies. Chemokines, reflecting their nom de guerre, control the recruitment of immune cells as well as their interaction with tumour and stromal cells. Depending on their target cell selectivity, chemokines display either pro- or antitumour activities. For this Special Issue, we will capture the fast pace in cancer-related chemokine research. We particularly welcome contributions highlighting current research that goes well beyond prototype chemokine functions. Novel avenues with substantial translational potential include the crosstalk between chemokines and ICBs, the induction of resistance to therapy, the modulation of the tumour stroma, and direct effects on tumour cells, including growth, mobilisation, and dissemination. Reflecting these exciting developments, current clinical trials frequently include novel chemokine-targeted agents in combination with standard therapies.

Prof. Dr. Bernhard Moser
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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.

Keywords

  • chemokines
  • chemokine receptors
  • cancer immunotherapy
  • checkpoint blockade
  • cancer biomarkers
  • clinical trials

Published Papers (17 papers)

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Editorial

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3 pages, 190 KiB  
Editorial
Emerging Roles of Chemokines in Cancer Immunotherapy
by Bernhard Moser
Cancers 2022, 14(15), 3593; https://doi.org/10.3390/cancers14153593 - 23 Jul 2022
Cited by 1 | Viewed by 1164
Abstract
This series of 15 articles (4 original articles and 11 reviews) is presented by international leaders in chemokine research [...] Full article
(This article belongs to the Special Issue Emerging Roles of Chemokines in Cancer Immunotherapy)

Research

Jump to: Editorial, Review, Other

29 pages, 4528 KiB  
Article
Tumor Cell-Autonomous Pro-Metastatic Activities of PD-L1 in Human Breast Cancer Are Mediated by PD-L1-S283 and Chemokine Axes
by Nofar Erlichman, Tamir Baram, Tsipi Meshel, Dina Morein, Benny Da’adoosh and Adit Ben-Baruch
Cancers 2022, 14(4), 1042; https://doi.org/10.3390/cancers14041042 - 18 Feb 2022
Cited by 8 | Viewed by 2899 | Correction
Abstract
Therapies targeting the PD-L1/PD-1 axis have recently been introduced to triple-negative breast cancer (TNBC) with limited efficacy, suggesting that this axis promotes tumor progression through mechanisms other than immune suppression. Here, we over-expressed WT-PD-L1 in human TNBC cells (express endogenous PD-L1) and in [...] Read more.
Therapies targeting the PD-L1/PD-1 axis have recently been introduced to triple-negative breast cancer (TNBC) with limited efficacy, suggesting that this axis promotes tumor progression through mechanisms other than immune suppression. Here, we over-expressed WT-PD-L1 in human TNBC cells (express endogenous PD-L1) and in luminal-A breast cancer cells (no endogenous PD-L1 expression) and demonstrated that cell-autonomous PD-L1 activities lead to increased tumor cell growth, invasion and release of pro-metastatic factors (CXCL8, sICAM-1, GM-CSF). These activities were promoted by PD-1 and were inhibited by mutating S283 in PD-L1. Invasion of WT-PD-L1-cells required signaling by chemokine receptors CXCR1/2, CCR2 and CCR5 through autocrine circuits involving CXCL8, CCL2 and CCL5. Studies with T cell-deficient mice demonstrated that cell-autonomous WT-PD-L1 activities in TNBC cells increased tumor growth and metastasis compared to knock-out (KO)-PD-L1-cells, whereas S283A-PD-L1-expressing cells had minimal ability to form tumors and did not metastasize. Overall, our findings reveal autonomous and PD-1-induced tumor-promoting activities of PD-L1 that depend on S283 and on chemokine circuits. These results suggest that TNBC patients whose tumors express PD-L1 could benefit from therapies that prevent immune suppression by targeting PD-1/CTLA-4, alongside with antibodies to PD-L1, which would allow maximal impact by mainly targeting the cancer cells. Full article
(This article belongs to the Special Issue Emerging Roles of Chemokines in Cancer Immunotherapy)
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19 pages, 3356 KiB  
Article
The Omentum in Obesity-Associated Cancer: A Hindrance to Effective Natural Killer Cell Migration towards Tumour Which Can Be Overcome by CX3CR1 Antagonism
by Eimear Mylod, Fiona O’Connell, Noel E. Donlon, Christine Butler, John V. Reynolds, Joanne Lysaght and Melissa J. Conroy
Cancers 2022, 14(1), 64; https://doi.org/10.3390/cancers14010064 - 23 Dec 2021
Cited by 6 | Viewed by 3654
Abstract
Oesophagogastric adenocarcinomas (OAC) are obesity-associated malignancies, underpinned by severe immune dysregulation. We have previously shown that natural killer (NK) cells preferentially migrate to OAC omentum, where they undergo phenotypic and functional alterations and apoptosis. Furthermore, we have identified the CX3CR1:fractalkine (CX3CL1) pathway as [...] Read more.
Oesophagogastric adenocarcinomas (OAC) are obesity-associated malignancies, underpinned by severe immune dysregulation. We have previously shown that natural killer (NK) cells preferentially migrate to OAC omentum, where they undergo phenotypic and functional alterations and apoptosis. Furthermore, we have identified the CX3CR1:fractalkine (CX3CL1) pathway as pivotal in their recruitment to omentum. Here, we elucidate whether exposure to the soluble microenvironment of OAC omentum, and in particular fractalkine and IL-15 affects NK cell homing capacity towards oesophageal tumour. Our data uncover diminished NK cell migration towards OAC tumour tissue conditioned media (TCM) following exposure to omental adipose tissue conditioned media (ACM) and reveal that this migration can be rescued with CX3CR1 antagonist E6130. Furthermore, we show that fractalkine has opposing effects on NK cell migration towards TCM, when used alone or in combination with IL-15 and uncover its inhibitory effects on IL-15-mediated stimulation of death receptor ligand expression. Interestingly, treatment with fractalkine and/or IL-15 do not significantly affect NK cell adhesion to MAdCAM-1, despite changes they elicit to the expression of integrin α4β7. This study provides further evidence that CX3CR1 antagonism has therapeutic utility in rescuing NK cells from the deleterious effects of the omentum and fractalkine in OAC, thus limiting their dysfunction. Full article
(This article belongs to the Special Issue Emerging Roles of Chemokines in Cancer Immunotherapy)
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25 pages, 4552 KiB  
Article
The Chemokine-Based Peptide, CXCL9(74-103), Inhibits Angiogenesis by Blocking Heparan Sulfate Proteoglycan-Mediated Signaling of Multiple Endothelial Growth Factors
by Alexandra De Zutter, Helena Crijns, Nele Berghmans, Melissa García-Caballero, Lotte Vanbrabant, Noëmie Pörtner, Vincent Vanheule, Paulien Verscheure, Mohammad Mairaj Siddiquei, Ahmed M. Abu El-Asrar, Peter Carmeliet, Pieter Van Wielendaele, Ingrid De Meester, Jo Van Damme, Paul Proost and Sofie Struyf
Cancers 2021, 13(20), 5090; https://doi.org/10.3390/cancers13205090 - 12 Oct 2021
Cited by 11 | Viewed by 2459
Abstract
Growth factors such as vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF) and epidermal growth factor (EGF) are important angiogenesis-mediating factors. They exert their effects not only through their respective receptor tyrosine kinases (RTKs), but they also require molecular pairing with heparan [...] Read more.
Growth factors such as vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF) and epidermal growth factor (EGF) are important angiogenesis-mediating factors. They exert their effects not only through their respective receptor tyrosine kinases (RTKs), but they also require molecular pairing with heparan sulfate proteoglycans (HSPGs). Angiogenic growth factors and their signaling pathways are commonly targeted in current anti-angiogenic cancer therapies but have unfortunately insufficient impact on patient survival. Considering their obvious role in pathological angiogenesis, HS-targeting drugs have become an appealing new strategy. Therefore, we aimed to reduce angiogenesis through interference with growth factor-HS binding and downstream signaling using a CXCL9-derived peptide with a high affinity for glycosaminoglycans (GAGs), CXCL9(74-103). We showed that CXCL9(74-103) reduced EGF-, VEGF165- and FGF-2-mediated angiogenic processes in vitro, such as endothelial cell proliferation, chemotaxis, adhesion and sprouting, without exerting cell toxicity. CXCL9(74-103) interfered with growth factor signaling in diverse ways, e.g., by diminishing VEGF165 binding to HS and by direct association with FGF-2. The dependency of CXCL9(74-103) on HS for binding to HMVECs and for exerting its anti-angiogenic activity was also demonstrated. In vivo, CXCL9(74-103) attenuated neovascularization in the Matrigel plug assay, the corneal cauterization assay and in MDA-MB-231 breast cancer xenografts. Additionally, CXCL9(74-103) reduced vascular leakage in the retina of diabetic rats. In contrast, CXCL9(86-103), a peptide with low GAG affinity, showed no overall anti-angiogenic activity. Altogether, our results indicate that CXCL9(74-103) reduces angiogenesis by interfering with multiple HS-dependent growth factor signaling pathways. Full article
(This article belongs to the Special Issue Emerging Roles of Chemokines in Cancer Immunotherapy)
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18 pages, 3740 KiB  
Article
Contribution of Heparan Sulphate Binding in CCL21-Mediated Migration of Breast Cancer Cells
by Irene del Molino del Barrio, Annette Meeson, Katie Cooke, Mohammed Imad Malki, Ben Barron-Millar, John A. Kirby and Simi Ali
Cancers 2021, 13(14), 3462; https://doi.org/10.3390/cancers13143462 - 10 Jul 2021
Cited by 5 | Viewed by 2124
Abstract
Chemokine receptor CCR7 is implicated in the metastasis of breast cancer to the lymph nodes. Chemokine function is dependent upon their binding to both cell-surface heparan sulphate (HS) and to their specific receptors; thus, the role of HS in CCR7-mediated lymph node metastasis [...] Read more.
Chemokine receptor CCR7 is implicated in the metastasis of breast cancer to the lymph nodes. Chemokine function is dependent upon their binding to both cell-surface heparan sulphate (HS) and to their specific receptors; thus, the role of HS in CCR7-mediated lymph node metastasis was investigated by creating a non-HS binding chemokine CCL21 (mut-CCL21). Mut-CCL21 (Δ103–134) induced leukocyte chemotaxis in diffusion gradients but did not stimulate trans-endothelial migration of PBMCs (p < 0.001) and 4T1-Luc cells (p < 0.01). Furthermore, the effect of heparin and HS on the chemotactic properties of wild-type (WT) and mut-CCL21 was examined. Interestingly, heparin and HS completely inhibit the chemotaxis mediated by WT-CCL21 at 250 and 500 µg/mL, whereas minimal effect was seen with mut-CCL21. This difference could potentially be attributed to reduced HS binding, as surface plasmon resonance spectroscopy showed that mut-CCL21 did not significantly bind HS compared to WT-CCL21. A murine model was used to assess the potential of mut-CCL21 to prevent lymph node metastasis in vivo. Mice were injected with 4T1-Luc cells in the mammary fat pad and treated daily for a week with 20 µg mut-CCL21. Mice were imaged weekly with IVIS and sacrificed on day 18. Luciferase expression was significantly reduced in lymph nodes from mice that had been treated with mut-CCL21 compared to the control (p = 0.0148), suggesting the potential to target chemokine binding to HS as a therapeutic option. Full article
(This article belongs to the Special Issue Emerging Roles of Chemokines in Cancer Immunotherapy)
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Review

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13 pages, 1488 KiB  
Review
CXCR4/CXCL12 Activities in the Tumor Microenvironment and Implications for Tumor Immunotherapy
by Rosanna Mezzapelle, Manuela Leo, Francesca Caprioglio, Liam S. Colley, Andrea Lamarca, Lina Sabatino, Vittorio Colantuoni, Massimo P. Crippa and Marco E. Bianchi
Cancers 2022, 14(9), 2314; https://doi.org/10.3390/cancers14092314 - 6 May 2022
Cited by 30 | Viewed by 6656
Abstract
CXCR4 is a G-Protein coupled receptor that is expressed nearly ubiquitously and is known to control cell migration via its interaction with CXCL12, the most ancient chemokine. The functions of CXCR4/CXCL12 extend beyond cell migration and involve the recognition and disposal of unhealthy [...] Read more.
CXCR4 is a G-Protein coupled receptor that is expressed nearly ubiquitously and is known to control cell migration via its interaction with CXCL12, the most ancient chemokine. The functions of CXCR4/CXCL12 extend beyond cell migration and involve the recognition and disposal of unhealthy or tumor cells. The CXCR4/CXCL12 axis plays a relevant role in shaping the tumor microenvironment (TME), mainly towards dampening immune responses. Notably, CXCR4/CXCL12 cross-signal via the T and B cell receptors (TCR and BCR) and co-internalize with CD47, promoting tumor cell phagocytosis by macrophages in an anti-tumor immune process called ImmunoGenic Surrender (IGS). These specific activities in shaping the immune response might be exploited to improve current immunotherapies. Full article
(This article belongs to the Special Issue Emerging Roles of Chemokines in Cancer Immunotherapy)
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22 pages, 1933 KiB  
Review
The Chemokine System in Oncogenic Pathways Driven by Viruses: Perspectives for Cancer Immunotherapy
by Géraldine Schlecht-Louf, Claire Deback and Françoise Bachelerie
Cancers 2022, 14(3), 848; https://doi.org/10.3390/cancers14030848 - 8 Feb 2022
Cited by 4 | Viewed by 2958
Abstract
Chemokines interact with glycosaminoglycans of the extracellular matrix and activate heptahelical cellular receptors that mainly consist of G Protein-Coupled Receptors and a few atypical receptors also with decoy activity. They are well-described targets of oncogenic pathways and key players in cancer development, invasiveness, [...] Read more.
Chemokines interact with glycosaminoglycans of the extracellular matrix and activate heptahelical cellular receptors that mainly consist of G Protein-Coupled Receptors and a few atypical receptors also with decoy activity. They are well-described targets of oncogenic pathways and key players in cancer development, invasiveness, and metastasis acting both at the level of cancer cells and cells of the tumor microenvironment. Hence, they can regulate cancer cell proliferation and survival and promote immune or endothelial cell migration into the tumor microenvironment. Additionally, oncogenic viruses display the potential of jeopardizing the chemokine system by encoding mimics of chemokines and receptors as well as several products such as oncogenic proteins or microRNAs that deregulate their human host transcriptome. Conversely, the chemokine system participates in the host responses that control the virus life cycle, knowing that most oncoviruses establish asymptomatic latent infections. Therefore, the deregulated expression and function of chemokines and receptors as a consequence of acquired or inherited mutations could bias oncovirus infection toward pro-oncogenic pathways. We here review these different processes and discuss the anticancer therapeutic potential of targeting chemokine availability or receptor activation, from signaling to decoy-associated functions, in combination with immunotherapies. Full article
(This article belongs to the Special Issue Emerging Roles of Chemokines in Cancer Immunotherapy)
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19 pages, 759 KiB  
Review
Chemokines as Regulators of Neutrophils: Focus on Tumors, Therapeutic Targeting, and Immunotherapy
by Raffaella Bonecchi, Alberto Mantovani and Sebastien Jaillon
Cancers 2022, 14(3), 680; https://doi.org/10.3390/cancers14030680 - 28 Jan 2022
Cited by 11 | Viewed by 5037
Abstract
Neutrophils are an important component of the tumor microenvironment, and their infiltration has been associated with a poor prognosis for most human tumors. However, neutrophils have been shown to be endowed with both protumor and antitumor activities, reflecting their heterogeneity and plasticity in [...] Read more.
Neutrophils are an important component of the tumor microenvironment, and their infiltration has been associated with a poor prognosis for most human tumors. However, neutrophils have been shown to be endowed with both protumor and antitumor activities, reflecting their heterogeneity and plasticity in cancer. A growing body of studies has demonstrated that chemokines and chemokine receptors, which are fundamental regulators of neutrophils trafficking, can affect neutrophil maturation and effector functions. Here, we review human and mouse data suggesting that targeting chemokines or chemokine receptors can modulate neutrophil activity and improve their antitumor properties and the efficiency of immunotherapy. Full article
(This article belongs to the Special Issue Emerging Roles of Chemokines in Cancer Immunotherapy)
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17 pages, 5345 KiB  
Review
Chemokine Receptor-Targeted Therapies: Special Case for CCR8
by Bernhard Moser
Cancers 2022, 14(3), 511; https://doi.org/10.3390/cancers14030511 - 20 Jan 2022
Cited by 13 | Viewed by 5583
Abstract
Immune checkpoint blockade inhibitors (CBIs) targeting cytotoxic T lymphocyte associated protein-4 (CTLA-4) and program death receptor-1 (PD-1) or its ligand-1 (PD-L1) have transformed the outlook of many patients with cancer. This remarkable progress has highlighted, from the translational point of view, the importance [...] Read more.
Immune checkpoint blockade inhibitors (CBIs) targeting cytotoxic T lymphocyte associated protein-4 (CTLA-4) and program death receptor-1 (PD-1) or its ligand-1 (PD-L1) have transformed the outlook of many patients with cancer. This remarkable progress has highlighted, from the translational point of view, the importance of immune cells in the control of tumor progression. There is still room for improvement, since current CBI therapies benefit a minority of patients. Moreover, interference with immune checkpoint receptors frequently causes immune related adverse events (irAEs) with life-threatening consequences in some of the patients. Immunosuppressive cells in the tumor microenvironment (TME), including intratumoral regulatory T (Treg) cells, tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs), contribute to tumor progression and correlate with a negative disease outlook. Recent reports revealed the selective expression of the chemokine receptor CCR8 on tumor Treg cells, making CCR8 a promising target in translational research. In this review, I summarize our current knowledge about the cellular distribution and function of CCR8 in physiological and pathophysiological processes. The discussion includes an assessment of how the removal of CCR8-expressing cells might affect both anti-tumor immunity as well as immune homeostasis at remote sites. Based on these considerations, CCR8 appears to be a promising novel target to be considered in future translational research. Full article
(This article belongs to the Special Issue Emerging Roles of Chemokines in Cancer Immunotherapy)
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20 pages, 3735 KiB  
Review
Potential Role of CXCL13/CXCR5 Signaling in Immune Checkpoint Inhibitor Treatment in Cancer
by Ching-Hung Hsieh, Cheng-Zhe Jian, Liang-In Lin, Guan-Sian Low, Ping-Yun Ou, Chiun Hsu and Da-Liang Ou
Cancers 2022, 14(2), 294; https://doi.org/10.3390/cancers14020294 - 7 Jan 2022
Cited by 24 | Viewed by 6510
Abstract
Immune checkpoint inhibitors (ICIs), including antibodies that target programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), or cytotoxic T lymphocyte antigen 4 (CTLA4), represent some of the most important breakthroughs in new drug development for oncology therapy from the past decade. [...] Read more.
Immune checkpoint inhibitors (ICIs), including antibodies that target programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), or cytotoxic T lymphocyte antigen 4 (CTLA4), represent some of the most important breakthroughs in new drug development for oncology therapy from the past decade. CXC chemokine ligand 13 (CXCL13) exclusively binds CXC chemokine receptor type 5 (CXCR5), which plays a critical role in immune cell recruitment and activation and the regulation of the adaptive immune response. CXCL13 is a key molecular determinant of the formation of tertiary lymphoid structures (TLSs), which are organized aggregates of T, B, and dendritic cells that participate in the adaptive antitumor immune response. CXCL13 may also serve as a prognostic and predictive factor, and the role played by CXCL13 in some ICI-responsive tumor types has gained intense interest. This review discusses how CXCL13/CXCR5 signaling modulates cancer and immune cells to promote lymphocyte infiltration, activation by tumor antigens, and differentiation to increase the antitumor immune response. We also summarize recent preclinical and clinical evidence regarding the ICI-therapeutic implications of targeting the CXCL13/CXCR5 axis and discuss the potential role of this signaling pathway in cancer immunotherapy. Full article
(This article belongs to the Special Issue Emerging Roles of Chemokines in Cancer Immunotherapy)
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17 pages, 1798 KiB  
Review
Patient-Oriented Perspective on Chemokine Receptor Expression and Function in Glioma
by Damla Isci, Giulia D’Uonnolo, May Wantz, Bernard Rogister, Arnaud Lombard, Andy Chevigné, Martyna Szpakowska and Virginie Neirinckx
Cancers 2022, 14(1), 130; https://doi.org/10.3390/cancers14010130 - 28 Dec 2021
Cited by 7 | Viewed by 2279
Abstract
Gliomas are severe brain malignancies, with glioblastoma (GBM) being the most aggressive one. Despite continuous efforts for improvement of existing therapies, overall survival remains poor. Over the last years, the implication of chemokines and their receptors in GBM development and progression has become [...] Read more.
Gliomas are severe brain malignancies, with glioblastoma (GBM) being the most aggressive one. Despite continuous efforts for improvement of existing therapies, overall survival remains poor. Over the last years, the implication of chemokines and their receptors in GBM development and progression has become more evident. Recently, large amounts of clinical data have been made available, prompting us to investigate chemokine receptors in GBM from a still-unexplored patient-oriented perspective. This study aims to highlight and discuss the involvement of chemokine receptors—CCR1, CCR5, CCR6, CCR10, CX3CR1, CXCR2, CXCR4, ACKR1, ACKR2, and ACKR3—most abundantly expressed in glioma patients based on the analysis of publicly available clinical datasets. Given the strong intratumoral heterogeneity characterizing gliomas and especially GBM, receptor expression was investigated by glioma molecular groups, by brain region distribution, emphasizing tissue-specific receptor functions, and by cell type enrichment. Our study constitutes a clinically relevant and patient-oriented guide that recapitulates the expression profile and the complex roles of chemokine receptors within the highly diversified glioma landscape. Additionally, it strengthens the importance of patient-derived material for development and precise amelioration of chemokine receptor-targeting therapies. Full article
(This article belongs to the Special Issue Emerging Roles of Chemokines in Cancer Immunotherapy)
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23 pages, 1037 KiB  
Review
Chemokines in the Landscape of Cancer Immunotherapy: How They and Their Receptors Can Be Used to Turn Cold Tumors into Hot Ones?
by Nathan Karin
Cancers 2021, 13(24), 6317; https://doi.org/10.3390/cancers13246317 - 16 Dec 2021
Cited by 16 | Viewed by 6128
Abstract
Over the last decade, monoclonal antibodies to immune checkpoint inhibitors (ICI), also known as immune checkpoint blockers (ICB), have been the most successful approach for cancer therapy. Starting with mAb to cytotoxic T lymphocyte antigen 4 (CTLA-4) inhibitors in metastatic melanoma and continuing [...] Read more.
Over the last decade, monoclonal antibodies to immune checkpoint inhibitors (ICI), also known as immune checkpoint blockers (ICB), have been the most successful approach for cancer therapy. Starting with mAb to cytotoxic T lymphocyte antigen 4 (CTLA-4) inhibitors in metastatic melanoma and continuing with blockers of the interactions between program cell death 1 (PD-1) and its ligand program cell death ligand 1 (PDL-1) or program cell death ligand 2 (PDL-2), that have been approved for about 20 different indications. Yet for many cancers, ICI shows limited success. Several lines of evidence imply that the limited success in cancer immunotherapy is associated with attempts to treat patients with “cold tumors” that either lack effector T cells, or in which these cells are markedly suppressed by regulatory T cells (Tregs). Chemokines are a well-defined group of proteins that were so named due to their chemotactic properties. The current review focuses on key chemokines that not only attract leukocytes but also shape their biological properties. CXCR3 is a chemokine receptor with 3 ligands. We suggest using Ig-based fusion proteins of two of them: CXL9 and CXCL10, to enhance anti-tumor immunity and perhaps transform cold tumors into hot tumors. Potential differences between CXCL9 and CXCL10 regarding ICI are discussed. We also discuss the possibility of targeting the function or deleting a key subset of Tregs that are CCR8+ by monoclonal antibodies to CCR8. These cells are preferentially abundant in several tumors and are likely to be the key drivers in suppressing anti-cancer immune reactivity. Full article
(This article belongs to the Special Issue Emerging Roles of Chemokines in Cancer Immunotherapy)
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14 pages, 641 KiB  
Review
Suppressing MDSC Recruitment to the Tumor Microenvironment by Antagonizing CXCR2 to Enhance the Efficacy of Immunotherapy
by Kennady Bullock and Ann Richmond
Cancers 2021, 13(24), 6293; https://doi.org/10.3390/cancers13246293 - 15 Dec 2021
Cited by 24 | Viewed by 3452
Abstract
Myeloid-derived suppressor cells (MDSCs) are a heterogenous population of cells derived from immature myeloid cells. These cells are often associated with poor responses to cancer therapy, including immunotherapy, in a variety of tumor types. The C-X-C chemokine receptor 2 (CXCR2) signaling axis plays [...] Read more.
Myeloid-derived suppressor cells (MDSCs) are a heterogenous population of cells derived from immature myeloid cells. These cells are often associated with poor responses to cancer therapy, including immunotherapy, in a variety of tumor types. The C-X-C chemokine receptor 2 (CXCR2) signaling axis plays a key role in the migration of immunosuppressive MDSCs into the tumor microenvironment (TME) and the pre-metastatic niche. MDSCs impede the efficacy of immunotherapy through a variety of mechanisms. Efforts to target MDSCs by blocking CXCR2 is an active area of research as a method for improving existing and novel immunotherapy strategies. As immunotherapies gain approval for a wider array of clinical indications, it will become even more important to understand the efficacy of CXCR2 inhibition in combating immunotherapy resistance at different stages of tumor progression. Full article
(This article belongs to the Special Issue Emerging Roles of Chemokines in Cancer Immunotherapy)
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25 pages, 1683 KiB  
Review
Multifaceted Roles of Chemokines and Chemokine Receptors in Tumor Immunity
by Kazuhiko Matsuo, Osamu Yoshie and Takashi Nakayama
Cancers 2021, 13(23), 6132; https://doi.org/10.3390/cancers13236132 - 6 Dec 2021
Cited by 27 | Viewed by 3859
Abstract
Various immune cells are involved in host tumor immune responses. In particular, there are many T cell subsets with different roles in tumor immunity. T-helper (Th) 1 cells are involved in cellular immunity and thus play the major role in host anti-tumor immunity [...] Read more.
Various immune cells are involved in host tumor immune responses. In particular, there are many T cell subsets with different roles in tumor immunity. T-helper (Th) 1 cells are involved in cellular immunity and thus play the major role in host anti-tumor immunity by inducing and activating cytotoxic T lymphocytes (CTLs). On the other hand, Th2 cells are involved in humoral immunity and suppressive to Th1 responses. Regulatory T (Treg) cells negatively regulate immune responses and contribute to immune evasion of tumor cells. Th17 cells are involved in inflammatory responses and may play a role in tumor progression. However, recent studies have also shown that Th17 cells are capable of directly inducting CTLs and thus may promote anti-tumor immunity. Besides these T cell subsets, there are many other innate immune cells such as dendritic cells (DCs), natural killer (NK) cells, and myeloid-derived suppressor cells (MDSCs) that are involved in host immune responses to cancer. The migratory properties of various immune cells are critical for their functions and largely regulated by the chemokine superfamily. Thus, chemokines and chemokine receptors play vital roles in the orchestration of host immune responses to cancer. In this review, we overview the various immune cells involved in host responses to cancer and their migratory properties regulated by the chemokine superfamily. Understanding the roles of chemokines and chemokine receptors in host immune responses to cancer may provide new therapeutic opportunities for cancer immunotherapy. Full article
(This article belongs to the Special Issue Emerging Roles of Chemokines in Cancer Immunotherapy)
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20 pages, 1149 KiB  
Review
Chemokine Pathways in Cutaneous Melanoma: Their Modulation by Cancer and Exploitation by the Clinician
by Rebecca Adams, Bernhard Moser, Sophia N. Karagiannis and Katie E. Lacy
Cancers 2021, 13(22), 5625; https://doi.org/10.3390/cancers13225625 - 10 Nov 2021
Cited by 7 | Viewed by 2410
Abstract
The incidence of cutaneous malignant melanoma is rising globally and is projected to continue to rise. Advances in immunotherapy over the last decade have demonstrated that manipulation of the immune cell compartment of tumours is a valuable weapon in the arsenal against cancer; [...] Read more.
The incidence of cutaneous malignant melanoma is rising globally and is projected to continue to rise. Advances in immunotherapy over the last decade have demonstrated that manipulation of the immune cell compartment of tumours is a valuable weapon in the arsenal against cancer; however, limitations to treatment still exist. Cutaneous melanoma lesions feature a dense cell infiltrate, coordinated by chemokines, which control the positioning of all immune cells. Melanomas are able to use chemokine pathways to preferentially recruit cells, which aid their growth, survival, invasion and metastasis, and which enhance their ability to evade anticancer immune responses. Aside from this, chemokine signalling can directly influence angiogenesis, invasion, lymph node, and distal metastases, including epithelial to mesenchymal transition-like processes and transendothelial migration. Understanding the interplay of chemokines, cancer cells, and immune cells may uncover future avenues for melanoma therapy, namely: identifying biomarkers for patient stratification, augmenting the effect of current and emerging therapies, and designing specific treatments to target chemokine pathways, with the aim to reduce melanoma pathogenicity, metastatic potential, and enhance immune cell-mediated cancer killing. The chemokine network may provide selective and specific targets that, if included in current therapeutic regimens, harbour potential to improve outcomes for patients. Full article
(This article belongs to the Special Issue Emerging Roles of Chemokines in Cancer Immunotherapy)
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28 pages, 1636 KiB  
Review
CCR4 as a Therapeutic Target for Cancer Immunotherapy
by Osamu Yoshie
Cancers 2021, 13(21), 5542; https://doi.org/10.3390/cancers13215542 - 4 Nov 2021
Cited by 45 | Viewed by 8149
Abstract
CCR4 is a chemokine receptor mainly expressed by T cells. It is the receptor for two CC chemokine ligands, CCL17 and CCL22. Originally, the expression of CCR4 was described as highly selective for helper T type 2 (Th2) cells. Later, its expression was [...] Read more.
CCR4 is a chemokine receptor mainly expressed by T cells. It is the receptor for two CC chemokine ligands, CCL17 and CCL22. Originally, the expression of CCR4 was described as highly selective for helper T type 2 (Th2) cells. Later, its expression was extended to other T cell subsets such as regulatory T (Treg) cells and Th17 cells. CCR4 has long been regarded as a potential therapeutic target for allergic diseases such as atopic dermatitis and bronchial asthma. Furthermore, the findings showing that CCR4 is strongly expressed by T cell malignancies such as adult T cell leukemia/lymphoma (ATLL) and cutaneous T cell lymphomas (CTCLs) have led to the development and clinical application of the fully humanized and glyco-engineered monoclonal anti-CCR4 Mogamulizumab in refractory/relapsed ATLL and CTCLs with remarkable successes. However, Mogamulizumab often induces severe adverse events in the skin possibly because of its efficient depletion of Treg cells. In particular, treatment with Mogamulizumab prior to allogenic hematopoietic stem cell transplantation (allo-HSCT), the only curative option of these T cell malignancies, often leads to severe glucocorticoid-refractory graft-versus-host diseases. The efficient depletion of Treg cells by Mogamulizumab has also led to its clinical trials in advanced solid tumors singly or in combination with immune checkpoint inhibitors. The main focus of this review is CCR4; its expression on normal and malignant T cells and its significance as a therapeutic target in cancer immunotherapy. Full article
(This article belongs to the Special Issue Emerging Roles of Chemokines in Cancer Immunotherapy)
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1 pages, 153 KiB  
Correction
Correction: Erlichman et al. Tumor Cell-Autonomous Pro-Metastatic Activities of PD-L1 in Human Breast Cancer Are Mediated by PD-L1-S283 and Chemokine Axes. Cancers 2022, 14, 1042
by Nofar Erlichman, Tamir Baram, Tsipi Meshel, Dina Morein, Benny Da’adoosh and Adit Ben-Baruch
Cancers 2022, 14(11), 2579; https://doi.org/10.3390/cancers14112579 - 24 May 2022
Cited by 2 | Viewed by 969
Abstract
The authors apologize for several typos/technical inaccuracies in the original article [...] Full article
(This article belongs to the Special Issue Emerging Roles of Chemokines in Cancer Immunotherapy)
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