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Cells
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Tumor-Induced Immunosuppression
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Tumor-Induced Immunosuppression

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Immunology".

Deadline for manuscript submissions: closed (31 December 2020) | Viewed by 45094

Special Issue Editors

Dr. Paul A. Beavis

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Guest Editor
Peter MacCallum Canc Ctr, Canc Immunol Program, East Melbourne, VIC, Australia
Interests: immunosupression; adenosine; CAR T cells; immune checkpoint blockade
Dr. Fernando S. F. Guimaraes

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Guest Editor
Diamantina Institute, Translational Research Institute, University of Queensland, Brisbane, QLD 4102, Australia
Interests: immunoregulation; TGF-beta superfamily; NK cells; innate immunity
Dr. Imran House

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Guest Editor
Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
Interests: CRISPR/Cas9; cancer immunotherapy; tumour Immunology; CAR T cells; lymphocyte trafficking
Dr. Junyun Lai

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Guest Editor
Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
Interests: cancer immunotherapy; CAR T cells; dendritic cells; adoptive cell therapy
Dr. Camille Guillerey

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Guest Editor
Mater Research Institute, University of Queensland, Translational Research Institute, Woolloongabba, QLD, Australia
Interests: cancer immunology; hematological malignancies; immunotherapy; natural killer cells; dendritic cells
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The role of the immune system in cancer surveillance is now well established. The immune system acts to eliminate malignancies through immunosurveillance. Through a process known as immune escape, tumors can upregulate immunosuppressive pathways to prevent effective immune responses, resulting in tumor outgrowth and potentially metastasis.   Identifying the mechanisms of tumor-induced immunosuppression and developing therapeutics to overcome this has become a major focus in oncology. The potential of this approach is highlighted by the success of immune checkpoint inhibitors targeting CTLA-4, PD-1 or its cognate ligand PD-L1. There are now thousands of ongoing clinical trials either combining these therapeutics with other treatment modalities or evaluating novel immune-based therapies designed to overcome alternative suppression pathways.  Tumor-induced immunosuppression encompasses direct suppression of immune cells through ligand to ligand interactions, the secretion of immunosuppressive cytokines and metabolites, the establishment of a hypoxic environment that is unfavorable to effective antitumor immune responses, and the recruitment and differentiation of host immunosuppressive cells such as myeloid derived suppressor cells and regulatory T cells. Tumors can also suppress immune responses through the establishment of a niche which leads to the exclusion of immune cells, a so-called immune desert phenotype. This Special Issue will address the key barriers for effective antitumor immunity, approaches that have been developed to overcome them, and current clinical data using therapeutics developed to overcome immunosuppression. We hope this will provide a key resource for the field and provide insight into research areas which warrant further attention.

Dr. Paul A. Beavis
Dr. Fernando S. F. Guimaraes
Dr. Imran House
Dr. Junyun Lai
Dr. Camille Guillerey
Guest Editors

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells 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 2700 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 (10 papers)

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Research

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17 pages, 1763 KiB  
Article
Ovarian Cancer-Associated Ascites Have High Proportions of Cytokine-Responsive CD56bright NK Cells
by Cláudia Rodrigues Tonetti, Caroline Natânia de Souza-Araújo, Adriana Yoshida, Rodrigo Fernandes da Silva, Paulo César Martins Alves, Taís Nitsch Mazzola, Sophie Derchain, Luís Gustavo Romani Fernandes and Fernando Guimarães
Cells 2021, 10(7), 1702; https://doi.org/10.3390/cells10071702 - 06 Jul 2021
Cited by 10 | Viewed by 2937
Abstract
Ovarian cancer is the most lethal gynecological malignancy, with serous histotype as the most prevalent epithelial ovarian cancer (EOC). Peritoneal ascites is a frequent comorbidity in advanced EOC. EOC-associated ascites provide a reliable sampling source for studying lymphocytes directly from tumor environment. Herein, [...] Read more.
Ovarian cancer is the most lethal gynecological malignancy, with serous histotype as the most prevalent epithelial ovarian cancer (EOC). Peritoneal ascites is a frequent comorbidity in advanced EOC. EOC-associated ascites provide a reliable sampling source for studying lymphocytes directly from tumor environment. Herein, we carried out flow cytometry-based analysis to readdress issues on NK and T lymphocyte subsets in women with advanced EOC, additionally evaluating phenotypic modulation of their intracellular pathways involved in interleukin (IL)-2 and IL-15 signaling. Results depicted ascites as an inflammatory and immunosuppressive environment, presenting significantly (p < 0.0001) higher amounts of IL-6 and IL-10 than in the patients’ blood, as well as significantly (p < 0.05) increased expression of checkpoint inhibitory receptors (programmed death protein-1, PD-1) and ectonucleotidase (CD39) on T lymphocytes. However, NK lymphocytes from EOC-associated ascites showed higher (p < 0.05) pS6 phosphorylation compared with NK from blood. Additionally, in vitro treatment of lymphocytes with IL-2 or IL-15 elicited significantly (p < 0.001) phosphorylation of the STAT5 protein in NK, CD3 and CD8 lymphocytes, both from blood and ascites. EOC-associated ascites had a significantly (p < 0.0001) higher proportion of NK CD56bright lymphocytes than blood, which, in addition, were more responsive (p < 0.05) to stimulation by IL-2 than CD56dim NK. EOC-associated ascites allow studies on lymphocyte phenotype modulation in the tumor environment, where inflammatory profile contrasts with the presence of immunosuppressive elements and development of cellular self-regulating mechanisms. Full article
(This article belongs to the Special Issue Tumor-Induced Immunosuppression)
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11 pages, 64546 KiB  
Article
Pattern of Tumor-Infiltrating Lymphocytes in Mixed Epithelial and Stromal Tumor of the Kidney: A Review of Five Cases
by Hye Won Lee, Hyunwoo Lee, Chanho Park, Won Joon Oh, Tae Jin Kim, Ghee Young Kwon and Seong Il Seo
Cells 2021, 10(4), 917; https://doi.org/10.3390/cells10040917 - 16 Apr 2021
Viewed by 2186
Abstract
Mixed epithelial and stromal tumor of the kidney (MESTK), a benign rare tumor with malignant transformation potential, is thought to be derived from fetal or immature cells originating from the mesonephric and Müllerian ducts. However, due to its rarity, little is known about [...] Read more.
Mixed epithelial and stromal tumor of the kidney (MESTK), a benign rare tumor with malignant transformation potential, is thought to be derived from fetal or immature cells originating from the mesonephric and Müllerian ducts. However, due to its rarity, little is known about the anti-tumor immune responses in MESTK. Herein, we present five cases of MESTK and evaluate the population of tumor-infiltrating lymphocytes (TILs) using a freshly obtained MESTK sample. Microscopically, TILs were scattered or clustered in large aggregates in the stroma in all five cases; furthermore, three cases exhibited heavy, large lymphocytic aggregates with no well-organized tertiary lymphoid structures with germinal centers. Flow cytometric analysis of TILs in one freshly obtained MESTK sample revealed that >40% of CD3+ T cells were effector memory Fas+CD28− γδ T cells expressing high levels of programmed cell death protein 1 and inducible T-cell co-stimulator, but low levels of CD44 and CD27. Most αß T cells exhibited a naïve phenotype. Additionally, we detected many activated class-switched CD21+CD27+ B cells as well as CD11chighIgMhigh marginal zone B-like and CD27−CD21−CD23− immunoglobulin (Ig)DhighIgMlow age-associated B-like cells. Collectively, for the first time, we report the immune microenvironment pattern of MESTK to oncogenic stress. Full article
(This article belongs to the Special Issue Tumor-Induced Immunosuppression)
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18 pages, 2574 KiB  
Article
Combination of Photodynamic Therapy and a Flagellin-Adjuvanted Cancer Vaccine Potentiated the Anti-PD-1-Mediated Melanoma Suppression
by Hye Suk Hwang, Kondareddy Cherukula, Yong Jun Bang, Veena Vijayan, Myeong Ju Moon, Jayalakshmi Thiruppathi, Sao Puth, Yong Yeon Jeong, In-Kyu Park, Shee Eun Lee and Joon Haeng Rhee
Cells 2020, 9(11), 2432; https://doi.org/10.3390/cells9112432 - 07 Nov 2020
Cited by 33 | Viewed by 5648
Abstract
Immune checkpoint inhibitors become a standard therapy for malignant melanoma. As immune checkpoint inhibitor monotherapies proved to have limited efficacy in significant portion of patients, it is envisaged that combination with other therapeutic modalities may improve clinical outcomes. We investigated the effect of [...] Read more.
Immune checkpoint inhibitors become a standard therapy for malignant melanoma. As immune checkpoint inhibitor monotherapies proved to have limited efficacy in significant portion of patients, it is envisaged that combination with other therapeutic modalities may improve clinical outcomes. We investigated the effect of combining photodynamic therapy (PDT) and TLR5 agonist flagellin-adjuvanted tumor-specific peptide vaccination (FlaB-Vax) on the promotion of PD-1 blockade-mediated melanoma suppression using a mouse B16-F10 implantation model. Using a bilateral mouse melanoma cancer model, we evaluated the potentiation of PD-1 blockade by the combination of peritumoral FlaB-Vax delivery and PDT tumor ablation. A photosensitizing agent, pheophorbide A (PhA), was used for laser-triggered photodynamic destruction of the primary tumor. The effect of combination therapy in conjunction with PD-1 blockade was evaluated for tumor growth and survival. The effector cytokines that promote the activation of CD8+ T cells and antigen-presenting cells in tumor tissue and tumor-draining lymph nodes (TDLNs) were also assayed. PDT and FlaB-Vax combination therapy induced efficacious systemic antitumor immune responses for local and abscopal tumor control, with a significant increase in tumor-infiltrating effector memory CD8+ T cells and systemic IFNγ secretion. The combination of PDT and FlaB-Vax also enhanced the infiltration of tumor antigen-reactive CD8+ T cells and the accumulation of migratory CXCL10-secreting CD103+ dendritic cells (DCs) presumably contributing to tumor antigen cross-presentation in the tumor microenvironment (TME). The CD8+ T-cell-dependent therapeutic benefits of PDT combined with FlaB-Vax was significantly enhanced by a PD-1-targeting checkpoint inhibitor therapy. Conclusively, the combination of FlaB-Vax with PDT-mediated tumor ablation would serve a safe and feasible combinatorial therapy for enhancing PD-1 blockade treatment of malignant melanoma. Full article
(This article belongs to the Special Issue Tumor-Induced Immunosuppression)
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Review

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23 pages, 2582 KiB  
Review
PD-1 and LAG-3 Checkpoint Blockade: Potential Avenues for Therapy in B-Cell Lymphoma
by Joshua W. D. Tobin, Karolina Bednarska, Ashlea Campbell and Colm Keane
Cells 2021, 10(5), 1152; https://doi.org/10.3390/cells10051152 - 10 May 2021
Cited by 11 | Viewed by 4195
Abstract
The dependence of cancer on an immunotolerant tumor microenvironment (TME) is well established. Immunotherapies that overcome tumor-induced immune suppression have been central to recent advancements in oncology. This is highlighted by the success of agents that interrupt PD-1 mediated immune suppression in a [...] Read more.
The dependence of cancer on an immunotolerant tumor microenvironment (TME) is well established. Immunotherapies that overcome tumor-induced immune suppression have been central to recent advancements in oncology. This is highlighted by the success of agents that interrupt PD-1 mediated immune suppression in a range of cancers. However, while PD-1 blockade has been paradigm-shifting in many malignancies, the majority of cancers show high rates of primary resistance to this approach. This has led to a rapid expansion in therapeutic targeting of other immune checkpoint molecules to provide combination immune checkpoint blockade (ICB), with one such promising approach is blockade of Lymphocyte Activation Gene 3 (LAG-3). Clinically, lymphoproliferative disorders show a wide spectrum of responses to ICB. Specific subtypes including classical Hodgkin lymphoma have demonstrated striking efficacy with anti-PD-1 therapy. Conversely, early trials of ICB have been relatively disappointing in common subtypes of Non-Hodgkin lymphoma. In this review, we describe the TME of common lymphoma subtypes with an emphasis on the role of prominent immune checkpoint molecules PD-1 and LAG3. We will also discuss current clinical evidence for ICB in lymphoma and highlight key areas for further investigation where synergistic dual checkpoint blockade of LAG-3 and PD-1 could be used to overcome ICB resistance. Full article
(This article belongs to the Special Issue Tumor-Induced Immunosuppression)
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18 pages, 2625 KiB  
Review
Tissues and Tumor Microenvironment (TME) in 3D: Models to Shed Light on Immunosuppression in Cancer
by Teresa Ho and Rasha Msallam
Cells 2021, 10(4), 831; https://doi.org/10.3390/cells10040831 - 07 Apr 2021
Cited by 14 | Viewed by 6007
Abstract
Immunosuppression in cancer has emerged as a major hurdle to immunotherapy efforts. Immunosuppression can arise from oncogene-induced signaling within the tumor as well as from tumor-associated immune cells. Understanding various mechanisms by which the tumor can undermine and evade therapy is critical in [...] Read more.
Immunosuppression in cancer has emerged as a major hurdle to immunotherapy efforts. Immunosuppression can arise from oncogene-induced signaling within the tumor as well as from tumor-associated immune cells. Understanding various mechanisms by which the tumor can undermine and evade therapy is critical in improving current cancer immunotherapies. While mouse models have allowed for the characterization of key immune cell types and their role in tumor development, extrapolating these mechanisms to patients has been challenging. There is need for better models to unravel the effects of genetic alterations inherent in tumor cells and immune cells isolated from tumors on tumor growth and to investigate the feasibility of immunotherapy. Three-dimensional (3D) organoid model systems have developed rapidly over the past few years and allow for incorporation of components of the tumor microenvironment such as immune cells and the stroma. This bears great promise for derivation of patient-specific models in a dish for understanding and determining the impact on personalized immunotherapy. In this review, we will highlight the significance of current experimental models employed in the study of tumor immunosuppression and evaluate current tumor organoid-immune cell co-culture systems and their potential impact in shedding light on cancer immunosuppression. Full article
(This article belongs to the Special Issue Tumor-Induced Immunosuppression)
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25 pages, 760 KiB  
Review
The Role of Cytokines and Chemokines in Shaping the Immune Microenvironment of Glioblastoma: Implications for Immunotherapy
by Erica C. F. Yeo, Michael P. Brown, Tessa Gargett and Lisa M. Ebert
Cells 2021, 10(3), 607; https://doi.org/10.3390/cells10030607 - 09 Mar 2021
Cited by 31 | Viewed by 5241
Abstract
Glioblastoma is the most common form of primary brain tumour in adults. For more than a decade, conventional treatment has produced a relatively modest improvement in the overall survival of glioblastoma patients. The immunosuppressive mechanisms employed by neoplastic and non-neoplastic cells within the [...] Read more.
Glioblastoma is the most common form of primary brain tumour in adults. For more than a decade, conventional treatment has produced a relatively modest improvement in the overall survival of glioblastoma patients. The immunosuppressive mechanisms employed by neoplastic and non-neoplastic cells within the tumour can limit treatment efficacy, and this can include the secretion of immunosuppressive cytokines and chemokines. These factors can play a significant role in immune modulation, thus disabling anti-tumour responses and contributing to tumour progression. Here, we review the complex interplay between populations of immune and tumour cells together with defined contributions by key cytokines and chemokines to these intercellular interactions. Understanding how these tumour-derived factors facilitate the crosstalk between cells may identify molecular candidates for potential immunotherapeutic targeting, which may enable better tumour control and improved patient survival. Full article
(This article belongs to the Special Issue Tumor-Induced Immunosuppression)
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12 pages, 716 KiB  
Review
Targeting Myeloid-Derived Suppressor Cells in Ovarian Cancer
by Seiji Mabuchi, Tomoyuki Sasano and Naoko Komura
Cells 2021, 10(2), 329; https://doi.org/10.3390/cells10020329 - 05 Feb 2021
Cited by 24 | Viewed by 4616
Abstract
Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells that exhibit immunosuppressive activity. They also directly stimulate tumor cell proliferation, metastasis, and angiogenesis. In ovarian cancer, there are increased numbers of circulating or tumor-infiltrating MDSCs, and increased frequencies of MDSCs [...] Read more.
Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells that exhibit immunosuppressive activity. They also directly stimulate tumor cell proliferation, metastasis, and angiogenesis. In ovarian cancer, there are increased numbers of circulating or tumor-infiltrating MDSCs, and increased frequencies of MDSCs are associated with a poor prognosis or an advanced clinical stage. Moreover, in murine models of ovarian cancer, MDSC depletion has shown significant growth-inhibitory effects and enhanced the therapeutic efficacy of existing anticancer therapies. In this review, we summarize the current knowledge on MDSC biology, clinical significance of MDSC, and potential MDSC-targeting strategies in ovarian cancer. Full article
(This article belongs to the Special Issue Tumor-Induced Immunosuppression)
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19 pages, 1247 KiB  
Review
IL-1α Processing, Signaling and Its Role in Cancer Progression
by Jing Wen Chiu, Zuhairah Binte Hanafi, Lionel Chin Yong Chew, Yu Mei and Haiyan Liu
Cells 2021, 10(1), 92; https://doi.org/10.3390/cells10010092 - 07 Jan 2021
Cited by 30 | Viewed by 5171
Abstract
Interleukin-1α (IL-1α) is a major alarmin cytokine which triggers and boosts the inflammatory responses. Since its discovery in the 1940s, the structure and bioactivity of IL-1α has been extensively studied and emerged as a vital regulator in inflammation and hematopoiesis. IL-1α is translated [...] Read more.
Interleukin-1α (IL-1α) is a major alarmin cytokine which triggers and boosts the inflammatory responses. Since its discovery in the 1940s, the structure and bioactivity of IL-1α has been extensively studied and emerged as a vital regulator in inflammation and hematopoiesis. IL-1α is translated as a pro-form with minor bioactivity. The pro-IL-1α can be cleaved by several proteases to generate the N terminal and C terminal form of IL-1α. The C terminal form of IL-1α (mature form) has several folds higher bioactivity compared with its pro-form. IL-1α is a unique cytokine which could localize in the cytosol, membrane, nucleus, as well as being secreted out of the cell. However, the processing mechanism and physiological significance of these differentially localized IL-1α are still largely unknown. Accumulating evidence suggests IL-1α is involved in cancer pathogenesis. The role of IL-1α in cancer development is controversial as it exerts both pro- and anti-tumor roles in different cancer types. Here, we review the recent development in the processing and signaling of IL-1α and summarize the functions of IL-1α in cancer development. Full article
(This article belongs to the Special Issue Tumor-Induced Immunosuppression)
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32 pages, 2084 KiB  
Review
Fine-Tuning the Tumour Microenvironment: Current Perspectives on the Mechanisms of Tumour Immunosuppression
by Jesse D. Armitage, Hannah V. Newnes, Alison McDonnell, Anthony Bosco and Jason Waithman
Cells 2021, 10(1), 56; https://doi.org/10.3390/cells10010056 - 01 Jan 2021
Cited by 15 | Viewed by 4212
Abstract
Immunotherapy has revolutionised the treatment of cancers by harnessing the power of the immune system to eradicate malignant tissue. However, it is well recognised that some cancers are highly resistant to these therapies, which is in part attributed to the immunosuppressive landscape of [...] Read more.
Immunotherapy has revolutionised the treatment of cancers by harnessing the power of the immune system to eradicate malignant tissue. However, it is well recognised that some cancers are highly resistant to these therapies, which is in part attributed to the immunosuppressive landscape of the tumour microenvironment (TME). The contexture of the TME is highly heterogeneous and contains a complex architecture of immune, stromal, vascular and tumour cells in addition to acellular components such as the extracellular matrix. While understanding the dynamics of the TME has been instrumental in predicting durable responses to immunotherapy and developing new treatment strategies, recent evidence challenges the fundamental paradigms of how tumours can effectively subvert immunosurveillance. Here, we discuss the various immunosuppressive features of the TME and how fine-tuning these mechanisms, rather than ablating them completely, may result in a more comprehensive and balanced anti-tumour response. Full article
(This article belongs to the Special Issue Tumor-Induced Immunosuppression)
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14 pages, 982 KiB  
Review
Chronic Lymphocytic Leukemia-Induced Humoral Immunosuppression: A Systematic Review
by Ewelina Grywalska, Monika Zaborek, Jakub Łyczba, Rafał Hrynkiewicz, Dominika Bębnowska, Rafał Becht, Barbara Sosnowska-Pasiarska, Jolanta Smok-Kalwat, Marcin Pasiarski, Stanisław Góźdź, Jacek Roliński and Paulina Niedźwiedzka-Rystwej
Cells 2020, 9(11), 2398; https://doi.org/10.3390/cells9112398 - 02 Nov 2020
Cited by 12 | Viewed by 2992
Abstract
Secondary immunodeficiency is observed in all patients with chronic lymphocytic leukemia (CLL) in varying degrees. The aim of the study was to review the available literature data on patients with CLL, with particular regard to the pathogenesis of the disease and the impact [...] Read more.
Secondary immunodeficiency is observed in all patients with chronic lymphocytic leukemia (CLL) in varying degrees. The aim of the study was to review the available literature data on patients with CLL, with particular regard to the pathogenesis of the disease and the impact of humoral immunity deficiency on the clinical and therapeutic approach. A systematic literature review was carried out by two independent authors who searched PubMed databases for studies published up to January 2020. Additionally, Google Scholar was used to evaluate search results and support manual research. The search resulted in 240 articles eligible for analysis. After all criteria and filters were applied, 22 studies were finally applied to the analysis. The data analysis showed that the clinical heterogeneity of CLL patients correlates with the diversity of molecular abnormalities determining the clinical picture of the disease, the analysis of which enables setting therapeutic targets. Additionally, in improving the therapeutic method, it is worth introducing supportive therapies with the use of vaccines, antibiotics and/or immunoglobins. Moreover, humoral immunodeficiency in CLL has a strong influence on the risk of infection in patients for whom infections are a major cause of morbidity and mortality. Full article
(This article belongs to the Special Issue Tumor-Induced Immunosuppression)
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