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Role of epigenetic modifications in inhibitory immune checkpoints in cancer development and progression

Saleh, R; Toor, SM; Sasidharan Nair, V; Elkord, E

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Authors

R Saleh

SM Toor

V Sasidharan Nair

E Elkord



Abstract

A balance between co-inhibitory and co-stimulatory signals in the tumor microenvironment (TME) is critical to suppress tumor development and progression, primarily via maintaining effective immunosurveillance. Aberrant expression of immune checkpoints (ICs), including programmed cell death protein 1 (PD-1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), T cell immunoglobulin and mucin-domain containing-3 (TIM-3), lymphocyte-activation gene 3 (LAG-3) and T cell immunoreceptor with Ig and ITIM domains (TIGIT), can create an immune-subversive environment, which helps tumor cells to evade immune destruction. Recent studies showed that epigenetic modifications play critical roles in regulating the expression of ICs and their ligands in the TME. Reports showed that the promoter regions of genes encoding ICs/IC ligands can undergo inherent epigenetic alterations, such as DNA methylation and histone modifications (acetylation and methylation). These epigenetic aberrations can significantly contribute to the transcriptomic upregulation of ICs and their ligands. Epigenetic therapeutics, including DNA methyltransferase and histone deacetylase inhibitors, can be used to revert these epigenetic anomalies acquired during the progression of disease. These discoveries have established a promising therapeutic modality utilizing the combination of epigenetic and immunotherapeutic agents to restore the physiological epigenetic profile and to re-establish potent host immunosurveillance mechanisms. In this review, we highlight the roles of epigenetic modifications on the upregulation of ICs, focusing on tumor development, and progression. We discuss therapeutic approaches of epigenetic modifiers, including clinical trials in various cancer settings and their impact on current and future anti-cancer therapies.

Citation

Saleh, R., Toor, S., Sasidharan Nair, V., & Elkord, E. (2020). Role of epigenetic modifications in inhibitory immune checkpoints in cancer development and progression. Frontiers in Immunology, 11, 1469. https://doi.org/10.3389/fimmu.2020.01469

Journal Article Type Article
Acceptance Date Jun 5, 2020
Online Publication Date Jul 14, 2020
Publication Date Jul 14, 2020
Deposit Date Aug 4, 2020
Publicly Available Date Aug 4, 2020
Journal Frontiers in Immunology
Publisher Frontiers Media
Volume 11
Pages 1469
DOI https://doi.org/10.3389/fimmu.2020.01469
Keywords Immunology, cancer, immune checkpoints, epigenetics, DNA methylation, histone modifications, therapeutic targets
Publisher URL https://doi.org/10.3389/fimmu.2020.01469
Related Public URLs http://frontiersin.org/Immunology
Additional Information Additional Information : ** From Frontiers via Jisc Publications Router ** Licence for this article: http://creativecommons.org/licenses/by/4.0/ **Journal IDs: eissn 1664-3224 **History: published_online 14-07-2020; accepted 05-06-2020; submitted 22-03-2020; collection 2020
Funders : Qatar Biomedical Research Institute, Qatar Foundation

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