Epigenetic regulation of tumor immunity
Lizhi Pang, … , Amy B. Heimberger, Peiwen Chen
Lizhi Pang, … , Amy B. Heimberger, Peiwen Chen
Published June 17, 2024
Citation Information: J Clin Invest. 2024;134(12):e178540. https://doi.org/10.1172/JCI178540.
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Review

Epigenetic regulation of tumor immunity

Abstract

Although cancer has long been considered a genetic disease, increasing evidence shows that epigenetic aberrations play a crucial role in affecting tumor biology and therapeutic response. The dysregulated epigenome in cancer cells reprograms the immune landscape within the tumor microenvironment, thereby hindering antitumor immunity, promoting tumor progression, and inducing immunotherapy resistance. Targeting epigenetically mediated tumor-immune crosstalk is an emerging strategy to inhibit tumor progression and circumvent the limitations of current immunotherapies, including immune checkpoint inhibitors. In this Review, we discuss the mechanisms by which epigenetic aberrations regulate tumor-immune interactions and how epigenetically targeted therapies inhibit tumor progression and synergize with immunotherapy.

Authors

Lizhi Pang, Fei Zhou, Yang Liu, Heba Ali, Fatima Khan, Amy B. Heimberger, Peiwen Chen

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Figure 1

Epigenetic modulations in cancer cells regulate T cell biology.

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Epigenetic modulations in cancer cells regulate T cell biology. Under se...
Under selective pressure in the tumor microenvironment (TME), cancer cells exhibit high epigenetic heterogeneity. Aberrant expression of epigenetic enzymes (e.g., SETDB1, HDAC8, and MML4) in cancer cells regulate the expression of immunomodulatory genes (e.g., IFN genes, CCL4, and GSDMD) by catalyzing their classical substrates (e.g., H3K9, H3K27, and H3K4), which, in turn, affect the infiltration, activation, and cytotoxic function of T cells in the TME. Additionally, epigenetic regulators (e.g., KDM5B and KDM5D) in cancer cells also affect T cell antitumor immunity through noncanonical functions. Cancer cells take advantage of these epigenetic modulations to avoid CD8+ T cell surveillance, resulting in adaptive clonal expansion. Ac, acetyl group; CCL4, chemokine ligands 4; DNMT1/3a, DNA methyltransferases1/3a; GSDMD, gasdermin D; HDAC8, histone deacetylase 8; KDM5B/D, lysine demethylase 5B/D; Me, methyl group; MLL4, mixed-lineage leukemia 4; MMVL30, virus-like 30S; SETDB1, SET domain bifurcated histone lysine methyltransferase 1; TAP1/2, transporter associated with antigen processing 1/2.