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Immunoepigenetics: A Future Sentinel for Tumor Directed Therapies

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: closed (31 October 2020) | Viewed by 13035

Special Issue Editors


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Guest Editor
Dell Pediatric Research Institute, Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, 1400 Barbara Jordan Boulevard, Austin, TX 78723, USA
Interests: DNA damage and repair; DNA structure-induced genetic instability; mechanisms of mutagenesis; cancer etiology

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Guest Editor
Amity Centre of Translational Research, Amity University, Sector 125, Noida, India
Interests: pulmonary infection biology; tumor immunology/immunotherapy (lung and pancreatic cancer)

Special Issue Information

Dear Colleagues,

Both genetic and environmental factors are known to influence immune responses, particularly in disease. This is often due to epigenetic changes in the host, which modulate the differentiation and function of immune cells. Pathogen-derived factors (e.g., live viral particles) resulting from virotherapy and excessive use of TLR ligands (TLR mimicry) can contribute to alterations in the expression of key pathways, such as those involving IRF, STAT, TGF, TLRs, and HLA genes, which are paramount for proper functioning of the immune system. Alterations in the expression, splicing, and re-arrangement of various genes and in translation can contribute to autoimmunity. Epigenetic modifications of genes involved in the immune response can often render immune cells incapable of combating tumors. Recent studies have implicated epigenetic changes in the genes coding for CD40-40L, CD80, CD86, and ICAM-1 antigens and death-inducing receptors (e.g. PD-1) for the  inability of these molecules to activate immune responses and control tumor growth. Therefore, control of epigenetic changes in the host by the use of drugs targeting DNA methyltransferases and HDACs and of probiotics is believed to hold potential for stimulating host immune responses and eradicating tumors. The major aim and scope of this Special Issue is to discuss various recent modalities for the design of therapeutics to mitigate epigenetic changes for improved cancer therapies.

Prof. Dr. Karen M. Vasquez
Dr. Hridayesh Prakash
Guest Editors

Manuscript Submission Information

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Keywords

  • Immune-editing and tumor relapse
  • Histone modification and chemo/radioresistance
  • TLR polymorphism and immune evasion
  • HLA polymorphism and autoimmunity
  • Epigenesis and bystander toxicities

Published Papers (3 papers)

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Research

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11 pages, 1421 KiB  
Article
RX-3117 (Fluorocyclopentenyl-Cytosine)-Mediated Down-Regulation of DNA Methyltransferase 1 Leads to Protein Expression of Tumor-Suppressor Genes and Increased Functionality of the Proton-Coupled Folate Carrier
by Dzjemma Sarkisjan, Joris R. Julsing, Btissame El Hassouni, Richard J. Honeywell, Ietje Kathmann, Larry H. Matherly, Young B. Lee, Deog J. Kim and Godefridus J. Peters
Int. J. Mol. Sci. 2020, 21(8), 2717; https://doi.org/10.3390/ijms21082717 - 14 Apr 2020
Cited by 5 | Viewed by 2549
Abstract
(1) Background: RX-3117 (fluorocyclopentenyl-cytosine) is a cytidine analog that inhibits DNA methyltransferase 1 (DNMT1). We investigated the mechanism and potential of RX-3117 as a demethylating agent in several in vitro models. (2) Methods: we used western blotting to measure expression of several proteins [...] Read more.
(1) Background: RX-3117 (fluorocyclopentenyl-cytosine) is a cytidine analog that inhibits DNA methyltransferase 1 (DNMT1). We investigated the mechanism and potential of RX-3117 as a demethylating agent in several in vitro models. (2) Methods: we used western blotting to measure expression of several proteins known to be down-regulated by DNA methylation: O6-methylguanine-DNA methyltransferase (MGMT) and the tumor-suppressor genes, p16 and E-cadherin. Transport of methotrexate (MTX) mediated by the proton-coupled folate transporter (PCFT) was used as a functional assay. (3) Results: RX-3117 treatment decreased total DNA-cytosine-methylation in A549 non-small cell lung cancer (NSCLC) cells, and induced protein expression of MGMT, p16 and E-cadherin in A549 and SW1573 NSCLC cells. Leukemic CCRF-CEM cells and the MTX-resistant variant (CEM/MTX, with a deficient reduced folate carrier) have a very low expression of PCFT due to promoter hypermethylation. In CEM/MTX cells, pre-treatment with RX-3117 increased PCFT-mediated MTX uptake 8-fold, and in CEM cells 4-fold. With the reference hypomethylating agent 5-aza-2′-deoxycytidine similar values were obtained. RX-3117 also increased PCFT gene expression and PCFT protein. (4) Conclusion: RX-3117 down-regulates DNMT1, leading to hypomethylation of DNA. From the increased protein expression of tumor-suppressor genes and functional activation of PCFT, we concluded that RX-3117 might have induced hypomethylation of the promotor. Full article
(This article belongs to the Special Issue Immunoepigenetics: A Future Sentinel for Tumor Directed Therapies)
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Review

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20 pages, 1477 KiB  
Review
The Fate of Th17 Cells is Shaped by Epigenetic Modifications and Remodeled by the Tumor Microenvironment
by Elodie Renaude, Marie Kroemer, Romain Loyon, Delphine Binda, Christophe Borg, Michaël Guittaut, Eric Hervouet and Paul Peixoto
Int. J. Mol. Sci. 2020, 21(5), 1673; https://doi.org/10.3390/ijms21051673 - 29 Feb 2020
Cited by 29 | Viewed by 5890
Abstract
Th17 cells represent a subset of CD4+ T cells characterized by the master transcription factor RORγt and the production of IL-17. Epigenetic modifications such as post-translational histone modifications and DNA methylation play a key role in Th17 cell differentiation and high plasticity. Th17 [...] Read more.
Th17 cells represent a subset of CD4+ T cells characterized by the master transcription factor RORγt and the production of IL-17. Epigenetic modifications such as post-translational histone modifications and DNA methylation play a key role in Th17 cell differentiation and high plasticity. Th17 cells are highly recruited in many types of cancer and can be associated with good or bad prognosis. Here, we will review the remodeling of the epigenome induced by the tumor microenvironment, which may explain Th17 cell predominance. We will also discuss the promising treatment perspectives of molecules targeting epigenetic enzymes to remodel a Th17-enriched tumor microenvironment. Full article
(This article belongs to the Special Issue Immunoepigenetics: A Future Sentinel for Tumor Directed Therapies)
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27 pages, 1042 KiB  
Review
Targeting the Immune system and Epigenetic Landscape of Urological Tumors
by João Lobo, Carmen Jerónimo and Rui Henrique
Int. J. Mol. Sci. 2020, 21(3), 829; https://doi.org/10.3390/ijms21030829 - 28 Jan 2020
Cited by 15 | Viewed by 3988
Abstract
In the last years, we have witnessed remarkable advances in targeted therapies for cancer patients. There is a growing effort to either replace or reduce the dose of unspecific, systemic (chemo)therapies, given the associated short- and long-term side effects, by introducing more specific [...] Read more.
In the last years, we have witnessed remarkable advances in targeted therapies for cancer patients. There is a growing effort to either replace or reduce the dose of unspecific, systemic (chemo)therapies, given the associated short- and long-term side effects, by introducing more specific targeted therapies as single or combination agents. Due to the well-known implications of the immune system and epigenetic landscape in modulating cancer development, both have been explored as potential targets in several malignancies, including those affecting the genitourinary tract. As the immune system function is also epigenetically regulated, there is rationale for combining both strategies. However, this is still rather underexplored, namely in urological tumors. We aim to briefly review the use of immune therapies in prostate, kidney, bladder, and testicular cancer, and further describe studies providing supporting evidence on their combination with epigenetic-based therapies. Full article
(This article belongs to the Special Issue Immunoepigenetics: A Future Sentinel for Tumor Directed Therapies)
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