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The emerging role of epigenetic therapeutics in immuno-oncology

Abstract

The past decade has seen the emergence of immunotherapy as a prime approach to cancer treatment, revolutionizing the management of many types of cancer. Despite the promise of immunotherapy, most patients do not have a response or become resistant to treatment. Thus, identifying combinations that potentiate current immunotherapeutic approaches will be crucial. The combination of immune-checkpoint inhibition with epigenetic therapy is one such strategy that is being tested in clinical trials, encompassing a variety of cancer types. Studies have revealed key roles of epigenetic processes in regulating immune cell function and mediating antitumour immunity. These interactions make combined epigenetic therapy and immunotherapy an attractive approach to circumvent the limitations of immunotherapy alone. In this Review, we highlight the basic dynamic mechanisms underlying the synergy between immunotherapy and epigenetic therapies and detail current efforts to translate this knowledge into clinical benefit for patients.

Key points

  • The past decade has witnessed the emergence of immune-checkpoint inhibition as the potential fourth pillar of anticancer therapy; however, combination therapeutic paradigms are needed to maximize benefits and overcome resistance to immune-checkpoint inhibition.

  • Epigenetic therapy has the ability to modulate the tumour microenvironment, for example, by inducing both the accumulation and infiltration of CD8+ lymphocytes through interferon-dependent, chemokine-mediated chemotaxis.

  • Epigenetic therapy can also prevent the emergence and/or acquisition of an epigenetic programme of T cell exhaustion and can facilitate the formation of CD8+ effector and/or memory T cells.

  • Histone deacetylase inhibitors can affect the tumour myeloid compartment by causing myeloid-derived suppressor cell depletion, differentiation and functional antagonism.

  • Epigenetic modulators can enhance tumour cell recognition and potentiate type I interferon responses through MYC and MYC-related target downregulation.

  • The combination of epigenetic drugs and immunotherapy is emerging as a crucial therapeutic paradigm across a variety of malignancies.

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Fig. 1: Effects of epigenetic therapy on the immune state of a tumour and rationale for the use of combination epigenetic and immunotherapy strategies in cancer.
Fig. 2: Implications of DNA methylation-associated programmes on T cell differentiation.

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Acknowledgements

The work of the authors is supported by grants from The Dr Miriam and Sheldon G. Adelson Medical Research Foundation and the Defense Health Program through the Department of Defense Ovarian Cancer Research Program (Teal Innovator Award No. OC130454/W81XWH-14-1-0385). Opinions, interpretations, conclusions and recommendations presented in this manuscript are those of the author and are not necessarily endorsed by the Department of Defense. The authors also receive funding from The Hodson Trust (S.B.B.), the Commonwealth Foundation (S.B.B. and J.R.B.), the Emerson Cancer Research Award (S.B.B.), the Rising Tide Foundation for Clinical Research (S.B.B. and J.R.B.), the Stand Up To Cancer Jim Toth Sr Breakthrough Prize in Lung Cancer (S.B.B. and J.R.B.), the Van Andel Research Institute through the Van Andel Research Institute–Stand Up To Cancer Epigenetics Dream Team (to S.B.B.; Stand Up To Cancer is a program of the Entertainment Industry Foundation that is administered by AACR), and the NIH National Cancer Institute award number P30CA006973 (SKCCC Core Grant to S.B.B.). The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

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M.J.T., M.V. and S.B.B. researched data for the article and wrote the manuscript. All authors made substantial contribution to discussions of content and reviewed and/or edited the manuscript before submission.

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Correspondence to Stephen B. Baylin.

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S.B.B. is an inventor of the methylation-specific PCR platform, which is licensed to MDxHealth in agreement with Johns Hopkins University; S.B.B. and Johns Hopkins University are entitled to royalty sales shares. S.B.B. is on the Scientific Advisory Board for Mirati Therapeutics. J.R.B. is on advisory board/consultant for Amgen, BMS (uncompensated), Celgene, Genentech, Janssen Oncology, Lilly, Merck and Syndax. J.R.B. recieves grant research funding from AstraZeneca/MedImmune, BMS and Merck. K.A.M. is a consultant for AstraZeneca. All other authors declare no competing interests.

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Nature Reviews Clinical Oncology thanks M. Maio and the other, anonymous, reviewers for their contribution to the peer review of this work.

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Topper, M.J., Vaz, M., Marrone, K.A. et al. The emerging role of epigenetic therapeutics in immuno-oncology. Nat Rev Clin Oncol 17, 75–90 (2020). https://doi.org/10.1038/s41571-019-0266-5

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