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Mechanisms of Tumor Escape from Host Immunity

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A special issue of Vaccines (ISSN 2076-393X).

Deadline for manuscript submissions: closed (31 May 2016) | Viewed by 148031

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Prof. Dr. Theresa L. Whiteside

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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
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Dear Colleagues,

This special issue of Vaccines is aimed at reviewing different mechanisms operating in the tumor microenvironment (TME) that are responsible for tumor escape from the host immune system. These mechanisms have emerged and have been identified in the last two decades, providing us with a broad repertoire of factors, receptors, ligands and nanoparticles that contribute to dysfunction of anti-tumor immune cells in the TME. Recent efforts to develop, test, move to the clinic and evaluate benefits of therapeutic anti-tumor vaccines for patients with cancer have been largely frustrating. There may be many reasons for this lack of therapeutic success with anti-tumor vaccines in man. Nevertheless, the main obstacle seems to be the presence in the TME of inhibitory signals that interfere with functions of immune cells, especially targeting freshly-minted tumor antigen-specific T cells generated in response to anti-tumor vaccines. While the presence of immunoinhibitory factors in the TME that are either tumor-derived or produced by normal cells re-programed by the tumor is well recognized today, the diverse nature and individual profiles of existing immunosuppressive programs are only now being discovered. The large diversity of immunosuppressive mechanisms and molecular pathways they engage at the level of the tumor type, stage, differentiation and progression might be taken to indicate that each human tumor operates its own immunosuppressive strategy and that this strategy changes as the tumor progresses and metastasizes. This would suggest the immunosuppressive mechanisms operating in the TME are personalized. If this is the case, then understanding and silencing of the inhibitory mechanisms each individual tumor engages becomes a necessary component of any anti-tumor therapeutic strategy, including anti-tumor vaccines. The fate of immune cells in the TME as well as success of anti-tumor vaccines will be strictly dependent on the complete or partial elimination of the prevalent immunosuppressive mechanisms that the individual tumor operates. The current understanding of these mechanisms is not complete, and efforts to dissect and understand their molecular and cellular regulation are ongoing. The contributions in this special issue are expected to provide much needed insights into the complexity of mechanisms that allow for tumor escape from host immunity and that interfere with cancer immunotherapies.

Prof. Dr. Theresa L. Whiteside
Guest Editor

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Keywords

tumor microenvironment
immune suppression
checkpoint inhibition
inhibitory factors
regulatory T cells
regulatory B cells
myeloid-derived suppressor cells
exosomes

Published Papers (12 papers)

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Review

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Open AccessReview

The Escape of Cancer from T Cell-Mediated Immune Surveillance: HLA Class I Loss and Tumor Tissue Architecture

by Federico Garrido, Francisco Perea, Mónica Bernal, Abel Sánchez-Palencia, Natalia Aptsiauri and Francisco Ruiz-Cabello

Vaccines 2017, 5(1), 7; https://doi.org/10.3390/vaccines5010007 - 27 Feb 2017

Cited by 64 | Viewed by 8032

Abstract

Tumor immune escape is associated with the loss of tumor HLA class I (HLA-I) expression commonly found in malignant cells. Accumulating evidence suggests that the efficacy of immunotherapy depends on the expression levels of HLA class I molecules on tumors cells. It also depends on the molecular mechanism underlying the loss of HLA expression, which could be reversible/“soft” or irreversible/“hard” due to genetic alterations in HLA, β2-microglobulin or IFN genes. Immune selection of HLA-I negative tumor cells harboring structural/irreversible alterations has been demonstrated after immunotherapy in cancer patients and in experimental cancer models. Here, we summarize recent findings indicating that tumor HLA-I loss also correlates with a reduced intra-tumor T cell infiltration and with a specific reorganization of tumor tissue. T cell immune selection of HLA-I negative tumors results in a clear separation between the stroma and the tumor parenchyma with leucocytes, macrophages and other mononuclear cells restrained outside the tumor mass. Better understanding of the structural and functional changes taking place in the tumor microenvironment may help to overcome cancer immune escape and improve the efficacy of different immunotherapeutic strategies. We also underline the urgent need for designing strategies to enhance tumor HLA class I expression that could improve tumor rejection by cytotoxic T-lymphocytes (CTL). Full article

(This article belongs to the Special Issue Mechanisms of Tumor Escape from Host Immunity)

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Open AccessReview

Tumor Microenvironment Metabolism: A New Checkpoint for Anti-Tumor Immunity

by Nicole E. Scharping and Greg M. Delgoffe

Vaccines 2016, 4(4), 46; https://doi.org/10.3390/vaccines4040046 - 06 Dec 2016

Cited by 79 | Viewed by 9872

Abstract

When a T cell infiltrates a tumor, it is subjected to a variety of immunosuppressive and regulatory signals in the microenvironment. However, it is becoming increasingly clear that due to the proliferative and energetically-deregulated nature of tumor cells, T cells also operate at a metabolic disadvantage. The nutrient dearth of the tumor microenvironment (TME) creates “metabolic checkpoints” upon infiltrating T cells, impacting their ability to survive, proliferate and function effectively. In this review, we summarize the basics of tumor cell and T cell metabolism and discuss recent advances elucidating the individual metabolic checkpoints exerted on T cells that drive their dysfunction in the TME. Full article

(This article belongs to the Special Issue Mechanisms of Tumor Escape from Host Immunity)

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Open AccessReview

The Impact of Chemotherapy, Radiation and Epigenetic Modifiers in Cancer Cell Expression of Immune Inhibitory and Stimulatory Molecules and Anti-Tumor Efficacy

by Jessica Ann Chacon, Keith Schutsky and Daniel J. Powell

Vaccines 2016, 4(4), 43; https://doi.org/10.3390/vaccines4040043 - 14 Nov 2016

Cited by 34 | Viewed by 9972

Abstract

Genomic destabilizers, such as radiation and chemotherapy, and epigenetic modifiers are used for the treatment of cancer due to their apoptotic effects on the aberrant cells. However, these therapies may also induce widespread changes within the immune system and cancer cells, which may enable tumors to avoid immune surveillance and escape from host anti-tumor immunity. Genomic destabilizers can induce immunogenic death of tumor cells, but also induce upregulation of immune inhibitory ligands on drug-resistant cells, resulting in tumor progression. While administration of immunomodulatory antibodies that block the interactions between inhibitory receptors on immune cells and their ligands on tumor cells can mediate cancer regression in a subset of treated patients, it is crucial to understand how genomic destabilizers alter the immune system and malignant cells, including which inhibitory molecules, receptors and/or ligands are upregulated in response to genotoxic stress. Knowledge gained in this area will aid in the rational design of trials that combine genomic destabilizers, epigenetic modifiers and immunotherapeutic agents that may be synergized to improve clinical responses and prevent tumor escape from the immune system. Our review article describes the impact genomic destabilizers, such as radiation and chemotherapy, and epigenetic modifiers have on anti-tumor immunity and the tumor microenvironment. Although genomic destabilizers cause DNA damage on cancer cells, these therapies can also have diverse effects on the immune system, promote immunogenic cell death or survival and alter the cancer cell expression of immune inhibitor molecules. Full article

(This article belongs to the Special Issue Mechanisms of Tumor Escape from Host Immunity)

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Open AccessReview

Mesenchymal Stromal Cells Can Regulate the Immune Response in the Tumor Microenvironment

by Alessandro Poggi and Massimo Giuliani

Vaccines 2016, 4(4), 41; https://doi.org/10.3390/vaccines4040041 - 08 Nov 2016

Cited by 49 | Viewed by 17940

Abstract

The tumor microenvironment is a good target for therapy in solid tumors and hematological malignancies. Indeed, solid tumor cells’ growth and expansion can influence neighboring cells’ behavior, leading to a modulation of mesenchymal stromal cell (MSC) activities and remodeling of extracellular matrix components. This leads to an altered microenvironment, where reparative mechanisms, in the presence of sub-acute inflammation, are not able to reconstitute healthy tissue. Carcinoma cells can undergo epithelial mesenchymal transition (EMT), a key step to generate metastasis; these mesenchymal-like cells display the functional behavior of MSC. Furthermore, MSC can support the survival and growth of leukemic cells within bone marrow participating in the leukemic cell niche. Notably, MSC can inhibit the anti-tumor immune response through either carcinoma-associated fibroblasts or bone marrow stromal cells. Experimental data have indicated their relevance in regulating cytolytic effector lymphocytes of the innate and adaptive arms of the immune system. Herein, we will discuss some of the evidence in hematological malignancies and solid tumors. In particular, we will focus our attention on the means by which it is conceivable to inhibit MSC-mediated immune suppression and trigger anti-tumor innate immunity. Full article

(This article belongs to the Special Issue Mechanisms of Tumor Escape from Host Immunity)

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Open AccessReview

Targeting Immune Regulatory Networks to Counteract Immune Suppression in Cancer

by Chiara Camisaschi, Viviana Vallacchi, Elisabetta Vergani, Marcella Tazzari, Simona Ferro, Alessandra Tuccitto, Olga Kuchuk, Eriomina Shahaj, Roberta Sulsenti, Chiara Castelli, Monica Rodolfo, Licia Rivoltini and Veronica Huber

Vaccines 2016, 4(4), 38; https://doi.org/10.3390/vaccines4040038 - 04 Nov 2016

Cited by 20 | Viewed by 8136

Abstract

The onset of cancer is unavoidably accompanied by suppression of antitumor immunity. This occurs through mechanisms ranging from the progressive accumulation of regulatory immune cells associated with chronic immune stimulation and inflammation, to the expression of immunosuppressive molecules. Some of them are being successfully exploited as therapeutic targets, with impressive clinical results achieved in patients, as in the case of immune checkpoint inhibitors. To limit immune attack, tumor cells exploit specific pathways to render the tumor microenvironment hostile for antitumor effector cells. Local acidification might, in fact, anergize activated T cells and facilitate the accumulation of immune suppressive cells. Moreover, the release of extracellular vesicles by tumor cells can condition distant immune sites contributing to the onset of systemic immune suppression. Understanding which mechanisms may be prevalent in specific cancers or disease stages, and identifying possible strategies to counterbalance would majorly contribute to improving clinical efficacy of cancer immunotherapy. Here, we intend to highlight these mechanisms, how they could be targeted and the tools that might be available in the near future to achieve this goal. Full article

(This article belongs to the Special Issue Mechanisms of Tumor Escape from Host Immunity)

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Open AccessReview

Is There Still Room for Cancer Vaccines at the Era of Checkpoint Inhibitors

by Soumaya Karaki, Marie Anson, Thi Tran, Delphine Giusti, Charlotte Blanc, Stephane Oudard and Eric Tartour

Vaccines 2016, 4(4), 37; https://doi.org/10.3390/vaccines4040037 - 03 Nov 2016

Cited by 52 | Viewed by 9485

Abstract

Checkpoint inhibitor (CPI) blockade is considered to be a revolution in cancer therapy, although most patients (70%–80%) remain resistant to this therapy. It has been hypothesized that only tumors with high mutation rates generate a natural antitumor T cell response, which could be revigorated by this therapy. In patients with no pre-existing antitumor T cells, a vaccine-induced T cell response is a rational option to counteract clinical resistance. This hypothesis has been validated in preclinical models using various cancer vaccines combined with inhibitory pathway blockade (PD-1-PDL1-2, CTLA-4-CD80-CD86). Enhanced T cell infiltration of various tumors has been demonstrated following this combination therapy. The timing of this combination appears to be critical to the success of this therapy and multiple combinations of immunomodulating antibodies (CPI antagonists or costimulatory pathway agonists) have reinforced the synergy with cancer vaccines. Only limited results are available in humans and this combined approach has yet to be validated. Comprehensive monitoring of the regulation of CPI and costimulatory molecules after administration of immunomodulatory antibodies (anti-PD1/PD-L1, anti-CTLA-4, anti-OX40, etc.) and cancer vaccines should help to guide the selection of the best combination and timing of this therapy. Full article

(This article belongs to the Special Issue Mechanisms of Tumor Escape from Host Immunity)

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The Role of Myeloid-Derived Suppressor Cells (MDSC) in Cancer Progression

by Viktor Umansky, Carolin Blattner, Christoffer Gebhardt and Jochen Utikal

Vaccines 2016, 4(4), 36; https://doi.org/10.3390/vaccines4040036 - 03 Nov 2016

Cited by 284 | Viewed by 20924

Abstract

The immunosuppressive tumor microenvironment represents not only one of the key factors stimulating tumor progression but also a strong obstacle for efficient tumor immunotherapy. Immunosuppression was found to be associated with chronic inflammatory mediators including cytokines, chemokines and growth factors produced by cancer and stroma cells. Long-term intensive production of these factors induces the formation of myeloid-derived suppressor cells (MDSCs) representing one of the most important players mediating immunosuppression. Moreover, MDSCs could not only inhibit anti-tumor immune reactions but also directly stimulate tumor growth and metastasis. Therefore, understanding the mechanisms of their generation, expansion, recruitment and activation is required for the development of novel strategies for tumor immunotherapy. Full article

(This article belongs to the Special Issue Mechanisms of Tumor Escape from Host Immunity)

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Tumor-Derived Exosomes and Their Role in Tumor-Induced Immune Suppression

by Theresa L. Whiteside

Vaccines 2016, 4(4), 35; https://doi.org/10.3390/vaccines4040035 - 20 Oct 2016

Cited by 68 | Viewed by 7847

Abstract

Tumor-derived exosomes (TEX) are emerging as critical components of an intercellular information network between the tumor and the host. The tumor escapes from the host immune system by using a variety of mechanisms designed to impair or eliminate anti-tumor immunity. TEX carrying a cargo of immunoinhibitory molecules and factors represent one such mechanism. TEX, which are present in all body fluids of cancer patients, deliver negative molecular or genetic signals to immune cells re-programming their functions. Although TEX can also stimulate immune activity, in the microenvironments dominated by the tumor, TEX tend to mediate immune suppression thus promoting tumor progression. The TEX content, in part resembling that of the parent cell, may serve as a source of cancer biomarkers. TEX also interfere with immune therapies. A better understanding of TEX and their contribution to cancer progression and cancer patients’ response to immune therapies represents a challenging new field of investigation. Full article

(This article belongs to the Special Issue Mechanisms of Tumor Escape from Host Immunity)

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Neutrophils and Granulocytic MDSC: The Janus God of Cancer Immunotherapy

by Serena Zilio and Paolo Serafini

Vaccines 2016, 4(3), 31; https://doi.org/10.3390/vaccines4030031 - 09 Sep 2016

Cited by 56 | Viewed by 11755

Abstract

Neutrophils are the most abundant circulating blood cell type in humans, and are the first white blood cells recruited at the inflammation site where they orchestrate the initial immune response. Although their presence at the tumor site was recognized in the 1970s, until recently these cells have been neglected and considered to play just a neutral role in tumor progression. Indeed, in recent years neutrophils have been recognized to play a dual role in tumor development by either assisting the growth, angiogenesis, invasion, and metastasis or by exerting tumoricidal action directly via the secretion of antitumoral compounds, or indirectly via the orchestration of antitumor immunity. Understanding the biology of these cells and influencing their polarization in the tumor micro- and macro-environment may be the key for the development of new therapeutic strategies, which may finally hold the promise of an effective immunotherapy for cancer. Full article

(This article belongs to the Special Issue Mechanisms of Tumor Escape from Host Immunity)

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Monitoring of the Immune Dysfunction in Cancer Patients

by Saskia J. A. M. Santegoets, Marij J. P. Welters and Sjoerd H. Van der Burg

Vaccines 2016, 4(3), 29; https://doi.org/10.3390/vaccines4030029 - 02 Sep 2016

Cited by 16 | Viewed by 7521

Abstract

Immunotherapy shows promising clinical results in patients with different types of cancer, but its full potential is not reached due to immune dysfunction as a result of several suppressive mechanisms that play a role in cancer development and progression. Monitoring of immune dysfunction is a prerequisite for the development of strategies aiming to alleviate cancer-induced immune suppression. At this point, the level at which immune dysfunction occurs has to be established, the underlying mechanism(s) need to be known, as well as the techniques to assess this. While it is relatively easy to measure general signs of immune suppression, it turns out that accurate monitoring of the frequency and function of immune-suppressive cells is still difficult. A lack of truly specific markers, the phenotypic complexity among suppressive cells of the same lineage, but potentially with different functions and functional assays that may not cover every mechanistic aspect of immune suppression are among the reasons complicating proper assessments. Technical innovations in flow and mass cytometry will allow for more complete sets of markers to precisely determine phenotype and associated function. There is, however, a clear need for functional assays that recapitulate more of the mechanisms employed to suppress the immune system. Full article

(This article belongs to the Special Issue Mechanisms of Tumor Escape from Host Immunity)

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Regulatory T Cells in the Tumor Microenvironment and Cancer Progression: Role and Therapeutic Targeting

by Belal Chaudhary and Eyad Elkord

Vaccines 2016, 4(3), 28; https://doi.org/10.3390/vaccines4030028 - 06 Aug 2016

Cited by 362 | Viewed by 16835

Abstract

Recent years have seen significant efforts in understanding and modulating the immune response in cancer. In this context, immunosuppressive cells, including regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), have come under intense investigation for their proposed roles in suppressing tumor-specific immune responses and establishing an immunosuppressive tumor microenvironment, thus enabling tumor immune evasion. Additionally, recent evidence indicates that Tregs comprise diverse and heterogeneous subsets; phenotypically and functionally distinct subsets of tumor-infiltrating Tregs could contribute differently to cancer prognosis and clinical outcomes. Understanding Treg biology in the setting of cancer, and specifically the tumor microenvironment, is important for designing effective cancer therapies. In this review, we critically examine the role of Tregs in the tumor microenvironment and in cancer progression focusing on human studies. We also discuss the impact of current therapeutic modalities on Treg biology and the therapeutic opportunities for targeting Tregs to enhance anti-tumor immune responses and clinical benefits. Full article

(This article belongs to the Special Issue Mechanisms of Tumor Escape from Host Immunity)

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The IL-8/IL-8R Axis: A Double Agent in Tumor Immune Resistance

by Justin M. David, Charli Dominguez, Duane H. Hamilton and Claudia Palena

Vaccines 2016, 4(3), 22; https://doi.org/10.3390/vaccines4030022 - 24 Jun 2016

Cited by 279 | Viewed by 18649

Abstract

Interleukin-8 (IL-8, CXCL8) is a pro-inflammatory chemokine produced by various cell types to recruit leukocytes to sites of infection or tissue injury. Acquisition of IL-8 and/or its receptors CXCR1 and CXCR2 are known to be a relatively common occurrence during tumor progression. Emerging research now indicates that paracrine signaling by tumor-derived IL-8 promotes the trafficking of neutrophils and myeloid-derived suppressor cells (MDSCs) into the tumor microenvironment, which have the ability to dampen anti-tumor immune responses. Furthermore, recent studies have also shown that IL-8 produced by the tumor mass can induce tumor cells to undergo the transdifferentiation process epithelial-to-mesenchymal transition (EMT) in which tumor cells shed their epithelial characteristics and acquire mesenchymal characteristics. EMT can increase metastatic dissemination, stemness, and intrinsic resistance, including to killing by cytotoxic immune cells. This review highlights the dual potential roles that the inflammatory cytokine IL-8 plays in promoting tumor resistance by enhancing the immunosuppressive microenvironment and activating EMT, and then discusses the potential for targeting the IL-8/IL-8 receptor axis to combat these various resistance mechanisms. Full article

(This article belongs to the Special Issue Mechanisms of Tumor Escape from Host Immunity)

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