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Review
. 2020 Sep;17(9):940-953.
doi: 10.1038/s41423-020-0505-9. Epub 2020 Jul 22.

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

Xingyi Pan  1   2   3   4   5 , Lei Zheng  6   7   8   9   10
Affiliations
Review

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

Xingyi Pan et al. Cell Mol Immunol. 2020 Sep.

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.

Keywords: Epigenetics; Immuno-modulation; Tumor microenvironment.

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Conflict of interest statement

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.

Figures

Fig. 1
Fig. 1
Stromal components within the tumor microenvironment. Major cell types include cancer-associated fibroblasts, macrophages, myeloid-derived suppressor cells, and lymphocytes
Fig. 2
Fig. 2
Epigenetic regulation in cancer-associated fibroblasts. a DNA methylation of SOCS1 regulated by DNMT1 and Shp-1 regulated by DNMT3B leads to gene repression, which activates STAT3 signaling during CAF differentiation and activation. DNA hypomethylation by TET, which leads to the upregulation of ADAM12, IL1A, CCL5, CCL26, CXCR4, and ICAM3 and triggers CAF differentiation. Decreased histone methylation regulated by EZH2 results in the upregulation of ADAMTS1 during CAF activation. Increased histone acetylation regulated by HDAC6 controls the upregulation of PGE2/COX2 during CAF activation. The chromatin remodeler Hmga2 is also induced to facilitate CAF activation. b Quiescent PSCs can be differentiated into either myCAFs or iCAFs, while myCAFs and iCAFs can also be reprogrammed interchangeably. MyCAFs can be induced by TGFβ signaling through direct contact with PDA tumor cells, while iCAFs can be induced by paracrine IL1a signaling through indirect interaction with tumor cells. MyCAFs have a cancer-promoting phenotype, while iCAFs have an immunosuppressive phenotype. DNA methylation of the IL1A and IL1B genes and their subsequent downregulation were observed in human MSCs cocultured with PDA tumor cells because of direct interaction, which potentially locked CAFs into the myCAF phenotype and prevented the transformation of myCAFs into iCAFs, supporting tumor growth
Fig. 3
Fig. 3
Epigenetic regulation in macrophages. DNMT3B is a negative regulator of M2. Tumor cells induced DNA methylation of NQO-1 and ALDH1A3, which promotes the M1–M2 transition. HMT PRMT1 is a positive regulator of M2 macrophages through induction of PPARγ. HMT SMYD3 is a positive regulator of M2 polarization. JMJD3, an H3K27 demethylase, is a positive regulator of M2 through its induction of Irf4, Arg1, and CD206. HDAC9 and HDAC11 are negative regulators of M2 polarization. HDAC SIRT2 and HDAC4 act as positive M2 regulators by inducing Gata3, Arg1, and Cd11c expression. Histone lactylation links metabolism with epigenetics in regulating M1 homeostasis and preventing M1–M2 macrophage transition in tumors. DNMT1 is a positive regulator of the M1 phenotype because it silences SOCS1. TET1 regulates M1 differentiation by promoting the overexpression of TNF-α. A reduced level of LSD1 is observed in M1 macrophages and is thought to maintain the M1 inflammatory gene expression signature. Glycolysis causes the accumulation of S-adenosylmethionine (SAM), which leads to increased histone H3K36 trimethylation for IL-1β production, which drives inflammatory macrophage differentiation. SIRT1/2 with DNMT3B prevent M1 activation through the repression of inflammatory genes
Fig. 4
Fig. 4
Epigenetic regulation in myeloid-derived suppressor cells. DNMT3A is upregulated in MDSCs and methylates genes, including S1PR4, RUNX1, IL1RN, and CCR2, to create unique DNA methylation patterns during MDSC differentiation. HDAC11 is a negative regulator of MDSC expansion/function. HMT SET1B controls MDSC function through upregulation of iNOS. HDAC activation facilitates immunosuppression and myeloid cell recruitment of immature MDSCs through the activation of ARG1, CCR2, and ITGAL. HDAC2 regulates MDSC differentiation and immunosuppressive function by modulating Rb1 expression. CBP/EP300-BRD, with its intrinsic histone acetyltransferase activity, reprograms tumor-associated MDSCs from expressing a suppressive to expressing an inflammatory phenotype through downregulation of STAT pathway-related genes such as Ly6C2, Ccr2, Mmp9, and NOS2 and the inhibition of Arg1 and iNOS
Fig. 5
Fig. 5
Epigenetic regulation of T lymphocytes. DNMT downregulation promotes Th1 polarization and activation of cytotoxic T cells because of the upregulation of IFNγ-stimulated genes, such as IFI27, IFI44, IFIT3, IFITM1, PSMB9, and IRF1. EZH2-mediated histone H3 lysine 27 trimethylation (H3K27me3) and DNA methyltransferase 1 (DNMT1)-mediated DNA methylation repress the expression of chemokines CXCL9 and CXCL10 and subsequently prevent effector T-cell trafficking to the TME. DNMT downregulation leads to the upregulation of signature genes in cytotoxic T cells, including PRF1, IFNG, GZMB, CCL3, CCL4, NKG7, and CST7, during naive T-cell to effector T-cell differentiation. Three inhibitory receptors, PDCD1, CTLA4, and LAG3, were found to be specifically demethylated within tumor-reactive CD8+ T cells and in late stages of T-cell subtype activation. HMT EZH2 negatively regulates the differentiation of memory T cells from effector T cells. Induction of acetyl-coenzyme A during aerobic glycolysis enhances the histone acetylation and transcriptional activation of Ifng in activated T cells. Histone deacetylase inhibition was shown to reprogram differentiated human CD8+ T cells into central memory-like T cells synergistically with IL21 and the upregulation of central memory T-cell surface CD28 and CD62L, showing a stable memory-associated transcriptional signature with increased Lef1 and Tcf7
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