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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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2020-07-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2020.01469/full |
| _version_ | 1818881022288199680 |
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| author | Reem Saleh Salman M. Toor Varun Sasidharan Nair Eyad Elkord Eyad Elkord |
| author_facet | Reem Saleh Salman M. Toor Varun Sasidharan Nair Eyad Elkord Eyad Elkord |
| author_sort | Reem Saleh |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-19T14:55:15Z |
| format | Article |
| id | doaj.art-ee4761e96bff449fae3d8fdcdca11611 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-19T14:55:15Z |
| publishDate | 2020-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-ee4761e96bff449fae3d8fdcdca116112022-12-21T20:16:44ZengFrontiers Media S.A.Frontiers in Immunology1664-32242020-07-011110.3389/fimmu.2020.01469544793Role of Epigenetic Modifications in Inhibitory Immune Checkpoints in Cancer Development and ProgressionReem Saleh0Salman M. Toor1Varun Sasidharan Nair2Eyad Elkord3Eyad Elkord4Cancer Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha, QatarCancer Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha, QatarCancer Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha, QatarCancer Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha, QatarBiomedical Research Center, School of Science, Engineering and Environment, University of Salford, Manchester, United KingdomA 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.https://www.frontiersin.org/article/10.3389/fimmu.2020.01469/fullcancerimmune checkpointsepigeneticsDNA methylationhistone modificationstherapeutic targets |
| spellingShingle | Reem Saleh Salman M. Toor Varun Sasidharan Nair Eyad Elkord Eyad Elkord Role of Epigenetic Modifications in Inhibitory Immune Checkpoints in Cancer Development and Progression Frontiers in Immunology cancer immune checkpoints epigenetics DNA methylation histone modifications therapeutic targets |
| 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 | cancer immune checkpoints epigenetics DNA methylation histone modifications therapeutic targets |
| url | https://www.frontiersin.org/article/10.3389/fimmu.2020.01469/full |
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