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Mechanisms of Cancer Immunotherapy and Immune-Escape

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

Deadline for manuscript submissions: closed (15 September 2022) | Viewed by 24683

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Special Issue Editor

Dr. Geeta Upadhyay

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Guest Editor

Department of Pathology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA
Interests: cancer immune escape; targeted therapies; TGFbeta signaling; breast cancer; pancreatic cancer; antibodies; small molecules; CART therapies
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Cancer immunotherapy has led to a paradigm shift in cancer care and treatment. Cytotoxic T-lymphocytes (CTLs) can be activated against cancer cells by using immune checkpoint inhibitor antibodies such as anti-PD1, anti-PDL1, and anti-CTLA4. Engineered T-cell receptor (TCR) therapy and chimeric antigen receptor (CAR) T-cells attack cancer cells directly. Other types of immunotherapies, such as natural killer cell therapy, macrophage therapy, and vaccine therapy are in the clinical trials.

The results of immunotherapy in certain cancers have offered long-lasting remission while in other cancers it remains ineffective. The molecular markers associated with therapeutic outcomes of immunotherapy need to be defined. Cancer immunotherapy is highly personalized, with each patient displaying a unique response to the treatment, as observed by the extent of cancer regression and in the severity of side effects. The underlying causes of these differential outcomes rely on diverse yet interconnected mechanisms of immune tolerance that ultimately decide the fate of the cancer immunotherapy. Therefore, it is of the utmost importance to better understand the mechanisms of immune-escape and immune-downregulation associated with cancer immunotherapy.

This Special Issue will highlight the current understanding of the “Mechanisms of Cancer Immunotherapy and Immune-Escape,” focused on the mechanisms of anti-cancer immunotherapeutic and its side effects, and describe novel outcome prediction biomarkers. The Special Issue will focus on understanding the immune-impact and mechanism of various traditional cancer therapies such as radiation therapy, chemotherapy, and antibody therapies that are known to invoke natural immune cells to act against cancer.

Dr. Geeta Upadhyay
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

immunotherapy
immune related adverse events and causes
clinical outcome
tumor microenvironment

Published Papers (5 papers)

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Research

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16 pages, 4554 KiB

Open AccessArticle

NSC243928 Treatment Induces Anti-Tumor Immune Response in Mouse Mammary Tumor Models

by Benson Chellakkan Selvanesan, Alvaro de Mingo Pulido, Sheelu Varghese, Deepak Rohila, Daniel Hupalo, Yuriy Gusev, Sara Contente, Matthew D. Wilkerson, Clifton L. Dalgard and Geeta Upadhyay

Cancers 2023, 15(5), 1468; https://doi.org/10.3390/cancers15051468 - 25 Feb 2023

Cited by 2 | Viewed by 1803

Abstract

NSC243928 induces cell death in triple-negative breast cancer cells in a LY6K-dependent manner. NSC243928 has been reported as an anti-cancer agent in the NCI small molecule library. The molecular mechanism of NSC243928 as an anti-cancer agent in the treatment of tumor growth in the syngeneic mouse model has not been established. With the success of immunotherapies, novel anti-cancer drugs that may elicit an anti-tumor immune response are of high interest in the development of novel drugs to treat solid cancer. Thus, we focused on studying whether NSC243928 may elicit an anti-tumor immune response in the in vivo mammary tumor models of 4T1 and E0771. We observed that NSC243928 induced immunogenic cell death in 4T1 and E0771 cells. Furthermore, NSC243928 mounted an anti-tumor immune response by increasing immune cells such as patrolling monocytes, NKT cells, B1 cells, and decreasing PMN MDSCs in vivo. Further studies are required to understand the exact mechanism of NSC243928 action in inducing an anti-tumor immune response in vivo, which can be used to determine a molecular signature associated with NSC243928 efficacy. NSC243928 may be a good target for future immuno-oncology drug development for breast cancer. Full article

(This article belongs to the Special Issue Mechanisms of Cancer Immunotherapy and Immune-Escape)

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20 pages, 42871 KiB

Open AccessArticle

Glioma Stem Cells Upregulate CD39 Expression to Escape Immune Response through SOX2 Modulation

by Bin Liu, Yufei Cao, Yanyan Li, Haifeng Ma, Mingfei Yang, Qiang Zhang, Guofeng Li, Kai Zhang, Yue Wu, Youxin Zhou, Wei Yang and Ting Sun

Cancers 2022, 14(3), 783; https://doi.org/10.3390/cancers14030783 - 03 Feb 2022

Cited by 6 | Viewed by 2309

Abstract

Ectonucleotidase CD39 hydrolyzing extracellular ATP (eATP) functions as a key modulator of immune response in the tumor microenvironment, yet the role of CD39 in contributing tumor stem cells in a more immunosuppressive microenvironment remains elusive. Here we report that the upregulation of CD39 is crucial for the decrease of extracellular ATP concentration around glioma stem cells (GSCs) to maintain an immunosuppressive microenvironment. Adriamycin (ADM) is able to promote the release of ATP, which recruits dendritic cells (DCs) to phagocytose GSCs. CD39 inhibition further increased extracellular ATP concentrations following ADM treatment and DCs phagocytosis. In addition, GSCs upregulated CD39 expression by SOX2-binding CD39 promotor. In mouse tumor models, the combination of ADM and CD39 blockade increased immune cell infiltration and reduced tumor size. These findings suggest that GSCs upregulate CD39 expression by their biological characteristics to maintain an immunosuppressive microenvironment, and CD39 inhibition supplies a favorable tumor microenvironment (TME) for immunotherapeutic intervention and enhances the immune response induced by chemotherapy. Full article

(This article belongs to the Special Issue Mechanisms of Cancer Immunotherapy and Immune-Escape)

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12 pages, 2939 KiB

Open AccessArticle

Pharmacological Activation of p53 during Human Monocyte to Macrophage Differentiation Attenuates Their Pro-Inflammatory Activation by TLR4, TLR7 and TLR8 Agonists

by Dmitry Namgaladze and Bernhard Brüne

Cancers 2021, 13(5), 958; https://doi.org/10.3390/cancers13050958 - 25 Feb 2021

Cited by 4 | Viewed by 2131

Abstract

The transcription factor p53 has well-recognized roles in regulating cell cycle, DNA damage repair, cell death, and metabolism. It is an important tumor suppressor and pharmacological activation of p53 by interrupting its interaction with the ubiquitin E3 ligase mouse double minute 2 homolog (MDM2) is actively explored for anti-tumor therapies. In immune cells, p53 modulates inflammatory responses, but the impact of p53 on macrophages remains incompletely understood. In this study, we used the MDM2 antagonist idasanutlin (RG7388) to investigate the responses of primary human macrophages to pharmacological p53 activation. Idasanutlin induced a robust p53-dependent transcriptional signature in macrophages, including several pro-apoptotic genes. However, idasanutlin did not generally sensitize macrophages to apoptosis, except for an enhanced response to a Fas-stimulating antibody. In fully differentiated macrophages, idasanutlin did not affect pro-inflammatory gene expression induced by toll-like receptor 4 (TLR4), TLR3, and TLR7/8 agonists, but inhibited interleukin-4-induced macrophage polarization. However, when present during monocyte to macrophage differentiation, idasanutlin attenuated inflammatory responses towards activation of TLR4 and TLR7/8 by low doses of lipopolysaccharide or resiquimod (R848). This was accompanied by a reduced expression of CD14, TLR7, and TLR8 in macrophages differentiated in the presence of idasanutlin. Our data suggest anti-inflammatory effects of pharmacological p53 activation in differentiating human macrophages. Full article

(This article belongs to the Special Issue Mechanisms of Cancer Immunotherapy and Immune-Escape)

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Review

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25 pages, 2087 KiB

Open AccessReview

Targeting SHIP1 and SHIP2 in Cancer

by Chiara Pedicone, Shea T. Meyer, John D. Chisholm and William G. Kerr

Cancers 2021, 13(4), 890; https://doi.org/10.3390/cancers13040890 - 20 Feb 2021

Cited by 15 | Viewed by 5283

Abstract

Membrane-anchored and soluble inositol phospholipid species are critical mediators of intracellular cell signaling cascades. Alterations in their normal production or degradation are implicated in the pathology of a number of disorders including cancer and pro-inflammatory conditions. The SH2-containing 5′ inositol phosphatases, SHIP1 and SHIP2, play a fundamental role in these processes by depleting PI(3,4,5)P₃, but also by producing PI(3,4)P₂ at the inner leaflet of the plasma membrane. With the intent of targeting SHIP1 or SHIP2 selectively, or both paralogs simultaneously, small molecule inhibitors and agonists have been developed and tested in vitro and in vivo over the last decade in various disease models. These studies have shown promising results in various pre-clinical models of disease including cancer and tumor immunotherapy. In this review the potential use of SHIP inhibitors in cancer is discussed with particular attention to the molecular structure, binding site and efficacy of these SHIP inhibitors. Full article

(This article belongs to the Special Issue Mechanisms of Cancer Immunotherapy and Immune-Escape)

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Graphical abstract

14 pages, 1339 KiB

Open AccessEditor’s ChoiceReview

Tumor Heterogeneity: A Great Barrier in the Age of Cancer Immunotherapy

by Nader El-Sayes, Alyssa Vito and Karen Mossman

Cancers 2021, 13(4), 806; https://doi.org/10.3390/cancers13040806 - 15 Feb 2021

Cited by 60 | Viewed by 11868

Abstract

Throughout the history of oncology research, tumor heterogeneity has been a major hurdle for the successful treatment of cancer. As a result of aberrant changes in the tumor microenvironment such as high mutational burden, hypoxic conditions and abnormal vasculature, several malignant subpopulations often exist within a single tumor mass. Therapeutic intervention can also increase selective pressure towards subpopulations with acquired resistance. This phenomenon is often the cause of relapse in previously responsive patients, drastically changing the expected outcome of therapy. In the case of cancer immunotherapy, tumor heterogeneity is a substantial barrier as acquired resistance often takes the form of antigen escape and immunosuppression. In an effort to combat intrinsic resistance mechanisms, therapies are often combined as a multi-pronged approach to target multiple pathways simultaneously. These multi-therapy regimens have long been a mainstay of clinical oncology with chemotherapy cocktails but are more recently being investigated in the emerging landscape of immunotherapy. Furthermore, as high throughput technology becomes more affordable and accessible, researchers continue to deepen their understanding of the factors that influence tumor heterogeneity and shape the TME over the course of treatment regimens. In this review, we will investigate the factors that give rise to tumor heterogeneity and the impact it has on the field of immunotherapy. We will discuss how tumor heterogeneity causes resistance to various treatments and review the strategies currently being employed to overcome this challenging clinical hurdle. Finally, we will outline areas of research that should be prioritized to gain a better understanding of tumor heterogeneity and develop appropriate solutions. Full article

(This article belongs to the Special Issue Mechanisms of Cancer Immunotherapy and Immune-Escape)

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