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Cancers
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Cancer-Induced Immune Suppression: An Achilles’ Heel of Current Immunotherapy
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Cancer-Induced Immune Suppression: An Achilles’ Heel of Current 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 (20 August 2020) | Viewed by 59471

Special Issue Editor

Prof. Dr. Theresa L. Whiteside

E-Mail Website
Guest Editor
1. UPMC Hillman Cancer Center, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15232, USA
2. Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
Interests: clinical cancer immunology; cancer immunotherapy; extracellular vesicles; immuno-oncology; immune suppression in cancer; regulatory T cells; tumor-derived exosomes; tumor microenvironment
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The concept of the immune surveillance of cancer is over 100 years old. It was first conceived by Paul Erlich, a Nobel-Prize-winning German physician who suggested that immune cells are endowed with a remarkable ability to recognize, target, seek, and destroy malignant cells. Erlich noted that the incidence of cancer would be considerably higher in the absence of these vigilant immune cells. It took decades for the scientific community to accept the existence of immune surveillance and to recognize that it was deficient or absent in most patients with cancer—especially those with advanced disease. Extensive phenotypic and functional analyses of tumor-infiltrating immune cells (TILs) in a variety of human tumor types indicated that TILs were functionally deficient and only regained the capability to mediate anti-tumor cytotoxicity after their removal from the TME. The notion that progressing tumors actively suppressed immune cells in the TME finally gained widespread attention approximately 15 years ago and has led to a flurry of mechanistic studies aimed at establishing the molecular underpinning of TIL immune dysfunction. These studies culminated in the discovery of PD-1/PD-L1 checkpoint inhibition and subsequent translation to the clinic of antibody-mediated blockade of this immune checkpoint. An unprecedented success of the immune checkpoint blockade (ICB) in patients with immune-cell-infiltrated (“hot”) tumors and its relative lack of therapeutic effects in patients with poorly-infiltrated (“cold”) tumors has once again called attention to the intimate relationship between the tumor and immune cells in the TME. It has become clear that human tumors utilize numerous and diverse strategies to escape from the host immune system. In addition to PD-1/PD-L1, other checkpoint inhibitory pathways operate in tumors, and various levels and flavors of suppression are uniquely associated with individual tumors and may determine therapeutic outcomes. Today, with more than 5 years of immune-oncology experience in the clinic, cancer-induced immune suppression is being acknowledged as a major barrier to successful cancer immunotherapy.

With increasing interest in the role tumor-induced immune suppression plays in immunotherapy outcome, it becomes critical to gather and review information available about the capability of tumors to interfere with the host immune system. Such knowledge could serve as a basis for the rational design of future clinical strategies. Moreover, there appear to be several interesting aspects of tumor-induced immune suppression that require attention: (a) it targets a variety of immune cell types; (b) it appears to favor activated immune cells; (c) it interferes with local and systemic immunity; (d) it engages a variety of established cellular mechanisms or pathways; (e) it selectively inhibits anti-tumor effector functions but does not lead to generalized immunodeficiency; and (f) it is closely related to tumor aggressiveness and progression. The mechanism or a sum of mechanisms underlying these various tumor-driven immune effects remains unknown. In this Special Issue, we will attempt to show why and how human tumors mange to create such remarkably powerful and highly personalized inhibitory environments. We will also discuss the potential for overcoming tumor-induced immune suppression by personalized approaches, where therapies could be selected and matched with the prevailing suppressive mechanisms for optimal therapeutic effects. Our major goal will be to convey the notion that a complete understanding of the nature of existing tumor-induced immune suppression in every cancer patient is achievable today and is necessary for the restoration of vigorous and effective anti-tumor immune responses.

Prof. Theresa L. Whiteside
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.

Published Papers (12 papers)

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Research

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19 pages, 1455 KiB  
Article
Tumor Microenvironment, HLA Class I and APM Expression in HPV-Negative Oral Squamous Cell Carcinoma
by Claudia Wickenhauser, Daniel Bethmann, Matthias Kappler, Alexander Walter Eckert, André Steven, Jürgen Bukur, Bernard Aloysius Fox, Jana Beer and Barbara Seliger
Cancers 2021, 13(4), 620; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13040620 - 04 Feb 2021
Cited by 12 | Viewed by 2267
Abstract
Progression of oral squamous cell carcinoma (OSCC) has been associated with an escape of tumor cells from the host immune surveillance due to an increased knowledge of its underlying molecular mechanisms and its modulation by the tumor microenvironment and immune cell repertoire. In [...] Read more.
Progression of oral squamous cell carcinoma (OSCC) has been associated with an escape of tumor cells from the host immune surveillance due to an increased knowledge of its underlying molecular mechanisms and its modulation by the tumor microenvironment and immune cell repertoire. In this study, the expression of HLA class I (HLA-I) antigens and of components of the antigen processing machinery (APM) was analyzed in 160 pathologically classified human papilloma virus (HPV)-negative OSCC lesions and correlated to the intra-tumoral immune cell response, IFN-γ signaling and to the patient’s outcome. A heterogeneous but predominantly lower constitutive protein expression of HLA-I APM components was found in OSCC sections when compared to non-neoplastic cells. Tumoral HLA-I APM component expression was further categorized into the three major phenotypes HLA-Ihigh/APMhigh, HLA-Ilow/APMlow and HLA-Idiscordant high/low/APMhigh. In the HLA-Ihigh/APMhigh group, the highest frequency of intra-tumoral CD8+ T cells and lowest number of CD8+ T cells close to FoxP3+ cells were found. Patients within this group presented the most unfavorable survival, which was significantly evident in stage T2 tumors. Despite a correlation with the number of intra-tumoral CD8+ T cells, tumoral JAK1 expression as a surrogate marker for IFN-γ signaling was not associated with HLA-I/APM expression. Thus, the presented findings strongly indicate the presence of additional factors involved in the immunomodulatory process of HPV-negative OSCC with a possible tumor-burden-dependent complex network of immune escape mechanisms beyond HLA-I/APM components and T cell infiltration in this tumor entity. Full article
(This article belongs to the Special Issue Cancer-Induced Immune Suppression: An Achilles’ Heel of Current Immunotherapy)
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19 pages, 3808 KiB  
Article
The CCR2/MCP-1 Chemokine Pathway and Lung Adenocarcinoma
by Payal Mittal, Liqing Wang, Tatiana Akimova, Craig A. Leach, Jose C. Clemente, Matthew R. Sender, Yao Chen, Brandon J. Turunen and Wayne W. Hancock
Cancers 2020, 12(12), 3723; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12123723 - 11 Dec 2020
Cited by 14 | Viewed by 2808
Abstract
Host anti-tumor immunity can be hindered by various mechanisms present within the tumor microenvironment, including the actions of myeloid-derived suppressor cells (MDSCs). We investigated the role of the CCR2/MCP-1 pathway in MDSC-associated tumor progression in murine lung cancer models. Phenotypic profiling revealed maximal [...] Read more.
Host anti-tumor immunity can be hindered by various mechanisms present within the tumor microenvironment, including the actions of myeloid-derived suppressor cells (MDSCs). We investigated the role of the CCR2/MCP-1 pathway in MDSC-associated tumor progression in murine lung cancer models. Phenotypic profiling revealed maximal expression of CCR2 by tumor-resident MDSCs, and MCP-1 by transplanted TC1 tumor cells, respectively. Use of CCR2-knockout (CCR2-KO) mice showed dependence of tumor growth on CCR2 signaling. Tumors in CCR2-KO mice had fewer CCR2low MDSCs, CD4 T cells and Tregs than WT mice, and increased infiltration by CD8 T cells producing IFN-γ and granzyme-B. Effects were MDSC specific, since WT and CCR2-KO conventional T (Tcon) cells had comparable proliferation and production of inflammatory cytokines, and suppressive functions of WT and CCR2-KO Foxp3+ Treg cells were also similar. We used a thioglycolate-induced peritonitis model to demonstrate a role for CCR2/MCP-1 in trafficking of CCR2+ cells to an inflammatory site, and showed the ability of a CCR2 antagonist to inhibit such trafficking. Use of this CCR2 antagonist promoted anti-tumor immunity and limited tumor growth. In summary, tumor cells are the prime source of MCP-1 that promotes MDSC recruitment, and our genetic and pharmacologic data demonstrate that CCR2 targeting may be an important component of cancer immunotherapy. Full article
(This article belongs to the Special Issue Cancer-Induced Immune Suppression: An Achilles’ Heel of Current Immunotherapy)
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16 pages, 1705 KiB  
Article
A Detailed Flow Cytometric Analysis of Immune Activity Profiles in Molecular Subtypes of Colorectal Cancer
by Xingru Li, Agnes Ling, Therese G. Kellgren, Marie Lundholm, Anna Löfgren-Burström, Carl Zingmark, Martin Rutegård, Ingrid Ljuslinder, Richard Palmqvist and Sofia Edin
Cancers 2020, 12(11), 3440; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12113440 - 19 Nov 2020
Cited by 8 | Viewed by 2209
Abstract
The local anti-tumour immune response has important prognostic value in colorectal cancer (CRC). In the era of immunotherapy, a better understanding of the immune response in molecular subgroups of CRC may lead to significant advances in personalised medicine. On this note, microsatellite instable [...] Read more.
The local anti-tumour immune response has important prognostic value in colorectal cancer (CRC). In the era of immunotherapy, a better understanding of the immune response in molecular subgroups of CRC may lead to significant advances in personalised medicine. On this note, microsatellite instable (MSI) tumours have been characterised by increased immune infiltration, suggesting MSI as a marker for immune inhibitor checkpoint therapy. Here, we used flow cytometry to perform a comprehensive analysis of immune activity profiles in tumour tissues, adjacent non-malignant tissues and blood, from a cohort of 69 CRC patients. We found several signs of immune suppression in tumours compared to adjacent non-malignant tissues, including T cells more often expressing the immune checkpoint molecules programmed cell death protein (PD-1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4). We further analysed immune cell infiltration in molecular subgroups of CRC. MSI tumours were indeed found to be associated with increased immune infiltration, including increased fractions of PD-1+ T cells. No correlation was, however, found between MSI and the fraction of CTLA-4+ T cells. Interestingly, within the group of patients with microsatellite stable (MSS) tumours, some also presented with increased immune infiltration, including comparably high portions of PD-1+ T cells, but also CTLA-4+ T cells. Furthermore, no correlation was found between PD-1+ and CTLA-4+ T cells, suggesting that different tumours may, to some extent, be regulated by different immune checkpoints. We further evaluated the distribution of immune activity profiles in the consensus molecular subtypes of CRC. In conclusion, our findings suggest that different immune checkpoint inhibitors may be beneficial for selected CRC patients irrespective of MSI status. Improved predictive tools are required to identify these patients. Full article
(This article belongs to the Special Issue Cancer-Induced Immune Suppression: An Achilles’ Heel of Current Immunotherapy)
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19 pages, 3660 KiB  
Article
IgE Activates Monocytes from Cancer Patients to Acquire a Pro-Inflammatory Phenotype
by Mano Nakamura, Elmira Amiri Souri, Gabriel Osborn, Roman Laddach, Jitesh Chauhan, Chara Stavraka, Sara Lombardi, Anna Black, Atousa Khiabany, Duaa O. Khair, Mariangela Figini, Anna Winship, Sharmistha Ghosh, Ana Montes, James F. Spicer, Heather J. Bax, Debra H. Josephs, Katie E. Lacy, Sophia Tsoka and Sophia N. Karagiannis
Cancers 2020, 12(11), 3376; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12113376 - 15 Nov 2020
Cited by 15 | Viewed by 3734
Abstract
IgE contributes to host-protective functions in parasitic and bacterial infections, often by monocyte and macrophage recruitment. We previously reported that monocytes contribute to tumour antigen-specific IgE-mediated tumour growth restriction in rodent models. Here, we investigate the impact of IgE stimulation on monocyte response, [...] Read more.
IgE contributes to host-protective functions in parasitic and bacterial infections, often by monocyte and macrophage recruitment. We previously reported that monocytes contribute to tumour antigen-specific IgE-mediated tumour growth restriction in rodent models. Here, we investigate the impact of IgE stimulation on monocyte response, cellular signalling, secretory and tumour killing functions. IgE cross-linking on human monocytes with polyclonal antibodies to mimic formation of immune complexes induced upregulation of co-stimulatory (CD40, CD80, CD86), and reduced expression of regulatory (CD163, CD206, MerTK) monocyte markers. Cross-linking and tumour antigen-specific IgE antibody-dependent cellular cytotoxicity (ADCC) of cancer cells by cancer patient-derived monocytes triggered release of pro-inflammatory mediators (TNFα, MCP-1, IL-10, CXCL-10, IL-1β, IL-6, IL-23). High intratumoural gene expression of these mediators was associated with favourable five-year overall survival in ovarian cancer. IgE cross-linking of trimeric FcεRI on monocytes stimulated the phosphorylation of intracellular protein kinases widely reported to be downstream of mast cell and basophil tetrameric FcεRI signalling. These included recently-identified FcεRI pathway kinases Fgr, STAT5, Yes and Lck, which we now associate with monocytes. Overall, anti-tumour IgE can potentiate pro-inflammatory signals, and prime tumour cell killing by human monocytes. These findings will inform the development of IgE monoclonal antibody therapies for cancer. Full article
(This article belongs to the Special Issue Cancer-Induced Immune Suppression: An Achilles’ Heel of Current Immunotherapy)
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17 pages, 14130 KiB  
Article
IL-2 and Anti-TGF-β Promote NK Cell Reconstitution and Anti-tumor Effects after Syngeneic Hematopoietic Stem Cell Transplantation
by Maite Alvarez, Cordelia Dunai, Lam T. Khuat, Ethan G. Aguilar, Isabel Barao and William J. Murphy
Cancers 2020, 12(11), 3189; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12113189 - 29 Oct 2020
Cited by 8 | Viewed by 2653
Abstract
The failure of autologous hematopoietic stem cell transplantation (HSCT) has been associated with a profound immunodeficiency that follows shortly after treatment, which renders patients susceptible to opportunistic infections and/or cancer relapse. Thus, given the additional immunosuppressive pathways involved in immune evasion in cancer, [...] Read more.
The failure of autologous hematopoietic stem cell transplantation (HSCT) has been associated with a profound immunodeficiency that follows shortly after treatment, which renders patients susceptible to opportunistic infections and/or cancer relapse. Thus, given the additional immunosuppressive pathways involved in immune evasion in cancer, strategies that induce a faster reconstitution of key immune effector cells are needed. Natural killer (NK) cells mediate potent anti-tumor effector functions and are the first immune cells to repopulate after HSCT. TGF-β is a potent immunosuppressive cytokine that can impede both the development and function of immune cells. Here, we evaluated the use of an immunotherapeutic regimen that combines low dose of IL-2, an NK cell stimulatory signal, with TGF-β neutralization, in order to accelerate NK cell reconstitution following congenic HSCT in mice by providing stimulatory signals yet also abrogating inhibitory ones. This therapy led to a marked expansion of NK cells and accelerated NK cell maturation. Following HSCT, mature NK cells from the treated recipients displayed an activated phenotype and enhanced anti-tumor responses both in vitro and in vivo. No overt toxicities or adverse effects were observed in the treated recipients. However, these stimulatory effects on NK cell recovery were predicated upon continuous treatment as cessation of treatment led to return to baseline levels and to no improvement of overall immune recovery when assessed at later time-points, indicating strict regulatory control of the NK cell compartment. Overall, this study still demonstrates that therapies that combine positive and negative signals can be plausible strategies to accelerate NK cell reconstitution following HSCT and augment anti-tumor efficacy. Full article
(This article belongs to the Special Issue Cancer-Induced Immune Suppression: An Achilles’ Heel of Current Immunotherapy)
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16 pages, 1315 KiB  
Article
Abundance of Regulatory T Cell (Treg) as a Predictive Biomarker for Neoadjuvant Chemotherapy in Triple-Negative Breast Cancer
by Masanori Oshi, Mariko Asaoka, Yoshihisa Tokumaru, Fernando A. Angarita, Li Yan, Ryusei Matsuyama, Emese Zsiros, Takashi Ishikawa, Itaru Endo and Kazuaki Takabe
Cancers 2020, 12(10), 3038; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12103038 - 19 Oct 2020
Cited by 77 | Viewed by 4038
Abstract
Regulatory CD4+ T cell (Treg), a subset of tumor-infiltrating lymphocytes (TILs), are known to suppress anticancer immunity but its clinical relevance in human breast cancer remains unclear. In this study, we estimated the relative abundance of Tregs in breast cancer of multiple [...] Read more.
Regulatory CD4+ T cell (Treg), a subset of tumor-infiltrating lymphocytes (TILs), are known to suppress anticancer immunity but its clinical relevance in human breast cancer remains unclear. In this study, we estimated the relative abundance of Tregs in breast cancer of multiple patient cohorts by using the xCell algorithm on bulk tumor gene expression data. In total, 5177 breast cancer patients from five independent cohorts (TCGA-BRCA, GSE96058, GSE25066, GSE20194, and GSE110590) were analyzed. Treg abundance was not associated with cancer aggressiveness, patient survival, or immune activity markers, but it was lower in metastatic tumors when compared to matched primary tumors. Treg was associated with a high mutation rate of TP53 genes and copy number mutations as well as with increased tumor infiltration of M2 macrophages and decreased infiltration of T helper type 1 (Th1) cells. Pathological complete response (pCR) after neoadjuvant chemotherapy (NAC) was significantly associated with low Treg abundance in triple negative breast cancer (TNBC) but not in ER-positive/Her2-negative subtype. High Treg abundance was significantly associated with high tumor expression of multiple immune checkpoint inhibitor genes. In conclusion, Treg abundance may have potential as a predictive biomarker of pCR after NAC in TNBC. Full article
(This article belongs to the Special Issue Cancer-Induced Immune Suppression: An Achilles’ Heel of Current Immunotherapy)
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13 pages, 1126 KiB  
Article
High PD-L1/CD274 Expression of Monocytes and Blood Dendritic Cells Is a Risk Factor in Lung Cancer Patients Undergoing Treatment with PD1 Inhibitor Therapy
by Dagmar Riemann, Wolfgang Schütte, Steffi Turzer, Barbara Seliger and Miriam Möller
Cancers 2020, 12(10), 2966; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12102966 - 13 Oct 2020
Cited by 15 | Viewed by 2885
Abstract
The aim of this study was to investigate the expression of the coinhibitory molecule PD-L1/CD274 in monocytes and dendritic cells (DC) in the blood of lung cancer patients undergoing PD1 inhibitor therapy and to correlate data with patient’s outcome. PD-L1/CD274 expression of monocytes, [...] Read more.
The aim of this study was to investigate the expression of the coinhibitory molecule PD-L1/CD274 in monocytes and dendritic cells (DC) in the blood of lung cancer patients undergoing PD1 inhibitor therapy and to correlate data with patient’s outcome. PD-L1/CD274 expression of monocytes, CD1c+ myeloid DC (mDC) and CD303+ plasmacytoid DC (pDC) was determined by flow cytometry in peripheral blood at immunotherapy onset. The predictive value of the PD-L1/CD274-expression data was determined by patients’ survival analysis. Patients with a high PD-L1/CD274 expression of monocytes and blood DC subpopulations rarely responded to PD1 inhibitor therapy. Low PD-L1/CD274 expression of monocytes and DC correlated with prolonged progression-free survival (PFS) as well as overall survival (OS). The highest PD-L1/CD274 expression was found in CD14+HLA-DR++CD16+ intermediate monocytes. Whereas the PD-L1/CD274 expression of monocytes and DC showed a strong positive correlation, only the PD-L1/CD274 expression of DC inversely correlated with DC amounts and lymphocyte counts in peripheral blood. Our results implicate that a high PD-L1/CD274 expression of blood monocytes and DC subtypes is a risk factor for therapy response and for the survival of lung cancer patients undergoing PD1 inhibitor therapy. Full article
(This article belongs to the Special Issue Cancer-Induced Immune Suppression: An Achilles’ Heel of Current Immunotherapy)
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14 pages, 2859 KiB  
Article
Purine Metabolites in Tumor-Derived Exosomes May Facilitate Immune Escape of Head and Neck Squamous Cell Carcinoma
by Nils Ludwig, Delbert G. Gillespie, Torsten E. Reichert, Edwin K. Jackson and Theresa L. Whiteside
Cancers 2020, 12(6), 1602; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12061602 - 17 Jun 2020
Cited by 41 | Viewed by 3639
Abstract
Body fluids of patients with head and neck squamous cell carcinoma (HNSCC) are enriched in exosomes that reflect properties of the tumor. The aim of this study was to determine whether purine metabolites are carried by exosomes and evaluate their role as potential [...] Read more.
Body fluids of patients with head and neck squamous cell carcinoma (HNSCC) are enriched in exosomes that reflect properties of the tumor. The aim of this study was to determine whether purine metabolites are carried by exosomes and evaluate their role as potential contributors to tumor immune escape. The gene expression levels of the purine synthesis pathway were studied using the Cancer Genome Atlas (TCGA) Head and Neck Cancer database. Exosomes were isolated from supernatants of UMSCC47 cells and from the plasma of HNSCC patients (n = 26) or normal donors (NDs; n = 5) using size exclusion chromatography. Ultraperformance liquid chromatography–tandem mass spectrometry (UPLC-MS/MS) was used to assess levels of 19 purine metabolites carried by exosomes. In HNSCC tissues, expression levels of genes involved in the purinergic pathway were upregulated indicating an accelerated purine metabolism compared to normal tissues. Exosomes from supernatants of UMSCC47 cells contained several purine metabolites, predominantly adenosine and inosine. Purine metabolite levels were enriched in exosomes isolated from the plasma of HNSCC patients compared to those isolated from NDs and carried elevated levels of adenosine (p = 0.0223). Exosomes of patients with early-stage disease and no lymph node metastasis contained significantly elevated levels of adenosine and 5′-GMP (p = 0.0247 and p = 0.0229, respectively). The purine metabolite levels in exosomes decreased in patients with advanced cancer and nodal involvement. This report provides the first evidence that HNSCC cells shuttle purine metabolites in exosomes, with immunosuppressive adenosine being the most prominent purine. Changes in the content and levels of purine metabolites in circulating exosomes reflect disease progression in HNSCC patients. Full article
(This article belongs to the Special Issue Cancer-Induced Immune Suppression: An Achilles’ Heel of Current Immunotherapy)
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Review

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33 pages, 971 KiB  
Review
Mechanisms of Immune Escape and Resistance to Checkpoint Inhibitor Therapies in Mismatch Repair Deficient Metastatic Colorectal Cancers
by Vito Amodio, Gianluca Mauri, Nicole M. Reilly, Andrea Sartore-Bianchi, Salvatore Siena, Alberto Bardelli and Giovanni Germano
Cancers 2021, 13(11), 2638; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13112638 - 27 May 2021
Cited by 34 | Viewed by 5635
Abstract
Immune checkpoint inhibitors (CPIs) represent an effective therapeutic strategy for several different types of solid tumors and are remarkably effective in mismatch repair deficient (MMRd) tumors, including colorectal cancer (CRC). The prevalent view is that the elevated and dynamic neoantigen burden associated with [...] Read more.
Immune checkpoint inhibitors (CPIs) represent an effective therapeutic strategy for several different types of solid tumors and are remarkably effective in mismatch repair deficient (MMRd) tumors, including colorectal cancer (CRC). The prevalent view is that the elevated and dynamic neoantigen burden associated with the mutator phenotype of MMRd fosters enhanced immune surveillance of these cancers. In addition, recent findings suggest that MMRd tumors have increased cytosolic DNA, which triggers the cGAS STING pathway, leading to interferon-mediated immune response. Unfortunately, approximately 30% of MMRd CRC exhibit primary resistance to CPIs, while a substantial fraction of tumors acquires resistance after an initial benefit. Profiling of clinical samples and preclinical studies suggests that alterations in the Wnt and the JAK-STAT signaling pathways are associated with refractoriness to CPIs. Intriguingly, mutations in the antigen presentation machinery, such as loss of MHC or Beta-2 microglobulin (B2M), are implicated in initial immune evasion but do not impair response to CPIs. In this review, we outline how understanding the mechanistic basis of immune evasion and CPI resistance in MMRd CRC provides the rationale for innovative strategies to increase the subset of patients benefiting from CPIs. Full article
(This article belongs to the Special Issue Cancer-Induced Immune Suppression: An Achilles’ Heel of Current Immunotherapy)
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32 pages, 1227 KiB  
Review
Highlighting the Potential for Chronic Stress to Minimize Therapeutic Responses to Radiotherapy through Increased Immunosuppression and Radiation Resistance
by Minhui Chen, Anurag K. Singh and Elizabeth A. Repasky
Cancers 2020, 12(12), 3853; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12123853 - 20 Dec 2020
Cited by 9 | Viewed by 3393
Abstract
Ionizing radiation has been used in the treatment of cancer for more than 100 years. While often very effective, there is still a great effort in place to improve the efficacy of radiation therapy for controlling the progression and recurrence of tumors. Recent [...] Read more.
Ionizing radiation has been used in the treatment of cancer for more than 100 years. While often very effective, there is still a great effort in place to improve the efficacy of radiation therapy for controlling the progression and recurrence of tumors. Recent research has revealed the close interaction between nerves and tumor progression, especially nerves of the autonomic nervous system that are activated by a variety of stressful stimuli including anxiety, pain, sleep loss or depression, each of which is likely to be increased in cancer patients. A growing literature now points to a negative effect of chronic stressful stimuli in tumor progression. In this review article, we present data on the potential for adrenergic stress to influence the efficacy of radiation and in particular, its potential to influence the anti-tumor immune response, and the frequency of an “abscopal effect” or the shrinkage of tumors which are outside an irradiated field. We conclude that chronic stress can be a major impediment to more effective radiation therapy through mechanisms involving immunosuppression and increased resistance to radiation-induced tumor cell death. Overall, these data highlight the potential value of stress reduction strategies to improve the outcome of radiation therapy. At the same time, objective biomarkers that can accurately and objectively reflect the degree of stress in patients over prolonged periods of time, and whether it is influencing immunosuppression and radiation resistance, are also critically needed. Full article
(This article belongs to the Special Issue Cancer-Induced Immune Suppression: An Achilles’ Heel of Current Immunotherapy)
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17 pages, 624 KiB  
Review
Characteristics of the Tumor Microenvironment That Influence Immune Cell Functions: Hypoxia, Oxidative Stress, Metabolic Alterations
by Ryan C. Augustin, Greg M. Delgoffe and Yana G. Najjar
Cancers 2020, 12(12), 3802; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12123802 - 17 Dec 2020
Cited by 66 | Viewed by 5875
Abstract
Immunotherapy (IMT) is now a core component of cancer treatment, however, many patients do not respond to these novel therapies. Investigating the resistance mechanisms behind this differential response is now a critical area of research. Immune-based therapies, particularly immune checkpoint inhibitors (ICI), rely [...] Read more.
Immunotherapy (IMT) is now a core component of cancer treatment, however, many patients do not respond to these novel therapies. Investigating the resistance mechanisms behind this differential response is now a critical area of research. Immune-based therapies, particularly immune checkpoint inhibitors (ICI), rely on a robust infiltration of T-cells into the tumor microenvironment (TME) for an effective response. While early efforts relied on quantifying tumor infiltrating lymphocytes (TIL) in the TME, characterizing the functional quality and degree of TIL exhaustion correlates more strongly with ICI response. Even with sufficient TME infiltration, immune cells face a harsh metabolic environment that can significantly impair effector function. These tumor-mediated metabolic perturbations include hypoxia, oxidative stress, and metabolites of cellular energetics. Primarily through HIF-1-dependent processes, hypoxia invokes an immunosuppressive phenotype via altered molecular markers, immune cell trafficking, and angiogenesis. Additionally, oxidative stress can promote lipid peroxidation, ER stress, and Treg dysfunction, all associated with immune dysregulation. Finally, the metabolic byproducts of lipids, amino acids, glucose, and cellular energetics are associated with immunosuppression and ICI resistance. This review will explore these biochemical pathways linked to immune cell dysfunction in the TME and highlight potential adjunctive therapies to be used alongside current IMT. Full article
(This article belongs to the Special Issue Cancer-Induced Immune Suppression: An Achilles’ Heel of Current Immunotherapy)
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33 pages, 2255 KiB  
Review
MHC Class I Downregulation in Cancer: Underlying Mechanisms and Potential Targets for Cancer Immunotherapy
by Annelisa M. Cornel, Iris L. Mimpen and Stefan Nierkens
Cancers 2020, 12(7), 1760; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12071760 - 02 Jul 2020
Cited by 189 | Viewed by 19361
Abstract
In recent years, major advances have been made in cancer immunotherapy. This has led to significant improvement in prognosis of cancer patients, especially in the hematological setting. Nonetheless, translation of these successes to solid tumors was found difficult. One major mechanism through which [...] Read more.
In recent years, major advances have been made in cancer immunotherapy. This has led to significant improvement in prognosis of cancer patients, especially in the hematological setting. Nonetheless, translation of these successes to solid tumors was found difficult. One major mechanism through which solid tumors can avoid anti-tumor immunity is the downregulation of major histocompatibility complex class I (MHC-I), which causes reduced recognition by- and cytotoxicity of CD8+ T-cells. Downregulation of MHC-I has been described in 40–90% of human tumors, often correlating with worse prognosis. Epigenetic and (post-)transcriptional dysregulations relevant in the stabilization of NFkB, IRFs, and NLRC5 are often responsible for MHC-I downregulation in cancer. The intrinsic reversible nature of these dysregulations provides an opportunity to restore MHC-I expression and facilitate adaptive anti-tumor immunity. In this review, we provide an overview of the mechanisms underlying reversible MHC-I downregulation and describe potential strategies to counteract this reduction in MHC-I antigen presentation in cancer. Full article
(This article belongs to the Special Issue Cancer-Induced Immune Suppression: An Achilles’ Heel of Current Immunotherapy)
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