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Role of Epigenetic Modifications in Inhibitory Immune Checkpoints in Cancer Development and Progression

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...

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Autores principales: Saleh, Reem, Toor, Salman M., Sasidharan Nair, Varun, Elkord, Eyad
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7371937/
https://www.ncbi.nlm.nih.gov/pubmed/32760400
http://dx.doi.org/10.3389/fimmu.2020.01469
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author Saleh, Reem
Toor, Salman M.
Sasidharan Nair, Varun
Elkord, Eyad
author_facet Saleh, Reem
Toor, Salman M.
Sasidharan Nair, Varun
Elkord, Eyad
author_sort Saleh, Reem
collection PubMed
description 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.
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spelling pubmed-73719372020-08-04 Role of Epigenetic Modifications in Inhibitory Immune Checkpoints in Cancer Development and Progression Saleh, Reem Toor, Salman M. Sasidharan Nair, Varun Elkord, Eyad Front Immunol Immunology 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. Frontiers Media S.A. 2020-07-14 /pmc/articles/PMC7371937/ /pubmed/32760400 http://dx.doi.org/10.3389/fimmu.2020.01469 Text en Copyright © 2020 Saleh, Toor, Sasidharan Nair and Elkord. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Saleh, Reem
Toor, Salman M.
Sasidharan Nair, Varun
Elkord, Eyad
Role of Epigenetic Modifications in Inhibitory Immune Checkpoints in Cancer Development and Progression
title Role of Epigenetic Modifications in Inhibitory Immune Checkpoints in Cancer Development and Progression
title_full Role of Epigenetic Modifications in Inhibitory Immune Checkpoints in Cancer Development and Progression
title_fullStr Role of Epigenetic Modifications in Inhibitory Immune Checkpoints in Cancer Development and Progression
title_full_unstemmed Role of Epigenetic Modifications in Inhibitory Immune Checkpoints in Cancer Development and Progression
title_short Role of Epigenetic Modifications in Inhibitory Immune Checkpoints in Cancer Development and Progression
title_sort role of epigenetic modifications in inhibitory immune checkpoints in cancer development and progression
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7371937/
https://www.ncbi.nlm.nih.gov/pubmed/32760400
http://dx.doi.org/10.3389/fimmu.2020.01469
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