DNA methyltransferase inhibition upregulates MHC-I to potentiate cytotoxic T lymphocyte responses in breast cancer.

Luo N, Nixon MJ, Gonzalez-Ericsson PI, Sanchez V, Opalenik SR, Li H, Zahnow CA, Nickels ML, Liu F, Tantawy MN, Sanders ME, Manning HC, Balko JM
Nat Commun. 2018 9 (1): 248

PMID: 29339738 · PMCID: PMC5770411 · DOI:10.1038/s41467-017-02630-w

Potentiating anti-tumor immunity by inducing tumor inflammation and T cell-mediated responses are a promising area of cancer therapy. Immunomodulatory agents that promote these effects function via a wide variety of mechanisms, including upregulation of antigen presentation pathways. Here, we show that major histocompatibility class-I (MHC-I) genes are methylated in human breast cancers, suppressing their expression. Treatment of breast cancer cell lines with a next-generation hypomethylating agent, guadecitabine, upregulates MHC-I expression in response to interferon-γ. In murine tumor models of breast cancer, guadecitabine upregulates MHC-I in tumor cells promoting recruitment of CD8+ T cells to the microenvironment. Finally, we show that MHC-I genes are upregulated in breast cancer patients treated with hypomethylating agents. Thus, the immunomodulatory effects of hypomethylating agents likely involve upregulation of class-I antigen presentation to potentiate CD8+ T cell responses. These strategies may be useful to potentiate anti-tumor immunity and responses to checkpoint inhibition in immune-refractory breast cancers.

MeSH Terms (15)

Animals Antineoplastic Agents Azacitidine Breast Neoplasms Cell Line, Tumor DNA (Cytosine-5-)-Methyltransferase 1 Female Gene Expression Regulation, Enzymologic Gene Expression Regulation, Neoplastic Genes, MHC Class I Humans Mammary Neoplasms, Experimental Mice Promoter Regions, Genetic T-Lymphocytes, Cytotoxic

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