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Epigenetics in modulating immune functions of stromal and immune cells in the tumor microenvironment

Cellular & Molecular Immunology volume 17, pages 940–953 (2020)Cite this article

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Abstract

Epigenetic regulation of gene expression in cancer cells has been extensively studied in recent decades, resulting in the FDA approval of multiple epigenetic agents for treating different cancer types. Recent studies have revealed novel roles of epigenetic dysregulation in altering the phenotypes of immune cells and tumor-associated stromal cells, including fibroblasts and endothelial cells. As a result, epigenetic dysregulation of these cells reshapes the tumor microenvironment (TME), changing it from an antitumor environment to an immunosuppressive environment. Here, we review recent studies demonstrating how specific epigenetic mechanisms drive aspects of stromal and immune cell differentiation with implications for the development of solid tumor therapeutics, focusing on the pancreatic ductal adenocarcinoma (PDA) TME as a representative of solid tumors. Due to their unique ability to reprogram the TME into a more immunopermissive environment, epigenetic agents have great potential for sensitizing cancer immunotherapy to augment the antitumor response, as an immunopermissive TME is a prerequisite for the success of cancer immunotherapy but is often not developed with solid tumors. The idea of combining epigenetic agents with cancer immunotherapy has been tested both in preclinical settings and in multiple clinical trials. In this review, we highlight the basic biological mechanisms underlying the synergy between epigenetic therapy and immunotherapy and discuss current efforts to translate this knowledge into clinical benefits for patients.

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Acknowledgements

This work was supported in part by NIH grant T32 CA126607 (L.Z.); NIH grant R01 CA169702 (L.Z.); NIH grant R01 CA197296 (L.Z.); the Viragh Foundation and the Skip Viragh Pancreatic Cancer Center at Johns Hopkins (L.Z.); the Sol Goldman Pancreatic Cancer Research Center (L.Z.); NCI SPORE P50 CA062924 (L.Z.); and Cancer Center Support Grant P30 CA006973.

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Authors and Affiliations

  1. The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Xingyi Pan & Lei Zheng

  2. Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Xingyi Pan & Lei Zheng

  3. Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Xingyi Pan & Lei Zheng

  4. The Pancreatic Cancer Precision Medicine Center of Excellence Program, The Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Xingyi Pan & Lei Zheng

  5. Cellular & Molecular Medicine Graduate Training Program, The Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Xingyi Pan & Lei Zheng

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  1. Xingyi Pan
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Correspondence to Lei Zheng.

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L.Z. receives grant support from Bristol-Myers Squibb, Merck, iTeos, Amgen, NovaRock, InxMed, and Halozyme. L.Z. is a paid consultant/Advisory Board Member at Biosion, Alphamab, NovaRock, Akrevia, DataRevive, and Mingruzhiyao. L.Z. holds shares of Alphamab and Mingruzhiyao.

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Pan, X., Zheng, L. Epigenetics in modulating immune functions of stromal and immune cells in the tumor microenvironment. Cell Mol Immunol 17, 940–953 (2020). https://doi.org/10.1038/s41423-020-0505-9

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