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Cancers
Special Issues
Epigenetics and Cancer Immunotherapy
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Epigenetics and Cancer Immunotherapy

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

Deadline for manuscript submissions: closed (30 January 2022) | Viewed by 18943

Special Issue Editor

Dr. Damiana Álvarez-Errico

E-Mail Website
Guest Editor
Josep Carreras Leukaemia Research Institute (IJC), 08916 Badalona, Spain
Interests: epigenomics; immunotherapy; functional genomics; inflammation

Special Issue Information

Dear Colleagues,

Tumor escape from the immune system relies on a variety of mechanisms, often based on a profound reorganization of tumor cell's epigenome, alteration of the tumor microenvironment (TME) and tumor-driven rewiring of immune cells chromatin landscape.  Immunotherapy has emerged as a therapeutic alternative to conventional drugs and has revolutionized cancer treatment, by boosting the patient´s anti-tumor immune response to effectively destroy the malignant cells and prevent cancer progression and expansion. There is growing evidence that epigenetic regulation has a key role in the modulation of anti-tumor immune responses by reshaping the TME and contributing to control immune recognition and immunogenicity. Tumor driven immune suppression can be overcome with epigenetic based drugs that inhibit the activity of epigenetic modifiers such DNA methyltransferase and histone deacetylases, promoting the expression of  tumour-associated antigens, immune checkpoint inhibitors, chemokines, and other immune-related genes. For that reason, the leverage of epigenetic changes controlling tumour-associated immune response to reinforce immunotherapy is a promising path of therapeutic intervention for cancer patients that deserves further investigation.

Dr. Damiana Álvarez-Errico
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
  • Epigenetics
  • Immune checkpoints
  • Anti-tumor response
  • Epigenetic drugs
  • T cell exhaustion

Published Papers (5 papers)

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Editorial

Jump to: Research, Review

2 pages, 176 KiB  
Editorial
Perspectives on Epigenetics and Cancer Immunotherapy: A Preface to Special Issue
by Damiana Alvarez-Errico
Cancers 2021, 13(6), 1452; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13061452 - 22 Mar 2021
Cited by 4 | Viewed by 1266
Abstract
The interaction of tumor cells with immune cells within the tumor microenvironment (TME) is the basis for several strategies of tumor evasion from immune surveillance, which nurture cancer development [...] Full article
(This article belongs to the Special Issue Epigenetics and Cancer Immunotherapy)

Research

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16 pages, 2096 KiB  
Article
TGF-β/SMAD Pathway Is Modulated by miR-26b-5p: Another Piece in the Puzzle of Chronic Lymphocytic Leukemia Progression
by Maria Elena Marquez, Sandra Sernbo, Eugenia Payque, Rita Uria, Juan Pablo Tosar, Juliana Querol, Catalina Berca, Angimar Uriepero, Daniel Prieto, Diego Alvarez-Saravia, Carolina Oliver, Victoria Irigoin, Gimena Dos Santos, Cecilia Guillermo, Ana Inés Landoni, Marcelo Navarrete, Florencia Palacios and Pablo Oppezzo
Cancers 2022, 14(7), 1676; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14071676 - 25 Mar 2022
Cited by 5 | Viewed by 2180
Abstract
Clinical and molecular heterogeneity are hallmarks of chronic lymphocytic leukemia (CLL), a neoplasm characterized by accumulation of mature and clonal long-lived CD5 + B-lymphocytes. Mutational status of the IgHV gene of leukemic clones is a powerful prognostic tool in CLL, and it is [...] Read more.
Clinical and molecular heterogeneity are hallmarks of chronic lymphocytic leukemia (CLL), a neoplasm characterized by accumulation of mature and clonal long-lived CD5 + B-lymphocytes. Mutational status of the IgHV gene of leukemic clones is a powerful prognostic tool in CLL, and it is well established that unmutated CLLs (U-CLLs) have worse evolution than mutated cases. Nevertheless, progression and treatment requirement of patients can evolve independently from the mutational status. Microenvironment signaling or epigenetic changes partially explain this different behavior. Thus, we think that detailed characterization of the miRNAs landscape from patients with different clinical evolution could facilitate the understanding of this heterogeneity. Since miRNAs are key players in leukemia pathogenesis and evolution, we aim to better characterize different CLL behaviors by comparing the miRNome of clinically progressive U-CLLs vs. stable U-CLLs. Our data show up-regulation of miR-26b-5p, miR-106b-5p, and miR-142-5p in progressive cases and indicate a key role for miR-26b-5p during CLL progression. Specifically, up-regulation of miR-26b-5p in CLL cells blocks TGF-β/SMAD pathway by down-modulation of SMAD-4, resulting in lower expression of p21−Cip1 kinase inhibitor and higher expression of c-Myc oncogene. This work describes a new molecular mechanism linking CLL progression with TGF-β modulation and proposes an alternative strategy to explore in CLL therapy. Full article
(This article belongs to the Special Issue Epigenetics and Cancer Immunotherapy)
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29 pages, 7518 KiB  
Article
Selective Targeting of Protein Kinase C (PKC)-θ Nuclear Translocation Reduces Mesenchymal Gene Signatures and Reinvigorates Dysfunctional CD8+ T Cells in Immunotherapy-Resistant and Metastatic Cancers
by Jenny Dunn, Robert D. McCuaig, Abel H. Y. Tan, Wen Juan Tu, Fan Wu, Kylie M. Wagstaff, Anjum Zafar, Sayed Ali, Himanshu Diwakar, Jane E. Dahlstrom, Elaine G. Bean, Jade K. Forwood, Sofiya Tsimbalyuk, Emily M. Cross, Kristine Hardy, Amanda L. Bain, Elizabeth Ahern, Riccardo Dolcetti, Roberta Mazzieri, Desmond Yip, Melissa Eastgate, Laeeq Malik, Peter Milburn, David A. Jans and Sudha Raoadd Show full author list remove Hide full author list
Cancers 2022, 14(6), 1596; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14061596 - 21 Mar 2022
Cited by 3 | Viewed by 4134
Abstract
Protein kinase C (PKC)-θ is a serine/threonine kinase with both cytoplasmic and nuclear functions. Nuclear chromatin-associated PKC-θ (nPKC-θ) is increasingly recognized to be pathogenic in cancer, whereas its cytoplasmic signaling is restricted to normal T-cell function. Here we show that nPKC-θ is enriched [...] Read more.
Protein kinase C (PKC)-θ is a serine/threonine kinase with both cytoplasmic and nuclear functions. Nuclear chromatin-associated PKC-θ (nPKC-θ) is increasingly recognized to be pathogenic in cancer, whereas its cytoplasmic signaling is restricted to normal T-cell function. Here we show that nPKC-θ is enriched in circulating tumor cells (CTCs) in patients with triple-negative breast cancer (TNBC) brain metastases and immunotherapy-resistant metastatic melanoma and is associated with poor survival in immunotherapy-resistant disease. To target nPKC-θ, we designed a novel PKC-θ peptide inhibitor (nPKC-θi2) that selectively inhibits nPKC-θ nuclear translocation but not PKC-θ signaling in healthy T cells. Targeting nPKC-θ reduced mesenchymal cancer stem cell signatures in immunotherapy-resistant CTCs and TNBC xenografts. PKC-θ was also enriched in the nuclei of CD8+ T cells isolated from stage IV immunotherapy-resistant metastatic cancer patients. We show for the first time that nPKC-θ complexes with ZEB1, a key repressive transcription factor in epithelial-to-mesenchymal transition (EMT), in immunotherapy-resistant dysfunctional PD1+/CD8+ T cells. nPKC-θi2 inhibited the ZEB1/PKC-θ repressive complex to induce cytokine production in CD8+ T cells isolated from patients with immunotherapy-resistant disease. These data establish for the first time that nPKC-θ mediates immunotherapy resistance via its activity in CTCs and dysfunctional CD8+ T cells. Disrupting nPKC-θ but retaining its cytoplasmic function may offer a means to target metastases in combination with chemotherapy or immunotherapy. Full article
(This article belongs to the Special Issue Epigenetics and Cancer Immunotherapy)
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Review

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17 pages, 1972 KiB  
Review
Epigenetic Regulation of Immunotherapy Response in Triple-Negative Breast Cancer
by Pere Llinàs-Arias, Sandra Íñiguez-Muñoz, Kelly McCann, Leonie Voorwerk, Javier I. J. Orozco, Miquel Ensenyat-Mendez, Borja Sesé, Maggie L. DiNome and Diego M. Marzese
Cancers 2021, 13(16), 4139; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13164139 - 17 Aug 2021
Cited by 11 | Viewed by 4218
Abstract
Triple-negative breast cancer (TNBC) is defined by the absence of estrogen receptor and progesterone receptor and human epidermal growth factor receptor 2 (HER2) overexpression. This malignancy, representing 15–20% of breast cancers, is a clinical challenge due to the lack of targeted treatments, higher [...] Read more.
Triple-negative breast cancer (TNBC) is defined by the absence of estrogen receptor and progesterone receptor and human epidermal growth factor receptor 2 (HER2) overexpression. This malignancy, representing 15–20% of breast cancers, is a clinical challenge due to the lack of targeted treatments, higher intrinsic aggressiveness, and worse outcomes than other breast cancer subtypes. Immune checkpoint inhibitors have shown promising efficacy for early-stage and advanced TNBC, but this seems limited to a subgroup of patients. Understanding the underlying mechanisms that determine immunotherapy efficiency is essential to identifying which TNBC patients will respond to immunotherapy-based treatments and help to develop new therapeutic strategies. Emerging evidence supports that epigenetic alterations, including aberrant chromatin architecture conformation and the modulation of gene regulatory elements, are critical mechanisms for immune escape. These alterations are particularly interesting since they can be reverted through the inhibition of epigenetic regulators. For that reason, several recent studies suggest that the combination of epigenetic drugs and immunotherapeutic agents can boost anticancer immune responses. In this review, we focused on the contribution of epigenetics to the crosstalk between immune and cancer cells, its relevance on immunotherapy response in TNBC, and the potential benefits of combined treatments. Full article
(This article belongs to the Special Issue Epigenetics and Cancer Immunotherapy)
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32 pages, 2511 KiB  
Review
The Next-Generation of Combination Cancer Immunotherapy: Epigenetic Immunomodulators Transmogrify Immune Training to Enhance Immunotherapy
by Reza Bayat Mokhtari, Manpreet Sambi, Bessi Qorri, Narges Baluch, Neda Ashayeri, Sushil Kumar, Hai-Ling Margaret Cheng, Herman Yeger, Bikul Das and Myron R. Szewczuk
Cancers 2021, 13(14), 3596; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13143596 - 18 Jul 2021
Cited by 12 | Viewed by 6029
Abstract
Cancer immunotherapy harnesses the immune system by targeting tumor cells that express antigens recognized by immune system cells, thus leading to tumor rejection. These tumor-associated antigens include tumor-specific shared antigens, differentiation antigens, protein products of mutated genes and rearrangements unique to tumor cells, [...] Read more.
Cancer immunotherapy harnesses the immune system by targeting tumor cells that express antigens recognized by immune system cells, thus leading to tumor rejection. These tumor-associated antigens include tumor-specific shared antigens, differentiation antigens, protein products of mutated genes and rearrangements unique to tumor cells, overexpressed tissue-specific antigens, and exogenous viral proteins. However, the development of effective therapeutic approaches has proven difficult, mainly because these tumor antigens are shielded, and cells primarily express self-derived antigens. Despite innovative and notable advances in immunotherapy, challenges associated with variable patient response rates and efficacy on select tumors minimize the overall effectiveness of immunotherapy. Variations observed in response rates to immunotherapy are due to multiple factors, including adaptative resistance, competency, and a diversity of individual immune systems, including cancer stem cells in the tumor microenvironment, composition of the gut microbiota, and broad limitations of current immunotherapeutic approaches. New approaches are positioned to improve the immune response and increase the efficacy of immunotherapies, highlighting the challenges that the current global COVID-19 pandemic places on the present state of immunotherapy. Full article
(This article belongs to the Special Issue Epigenetics and Cancer Immunotherapy)
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