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

• Published in: Nature communications 2018-01, Vol.9 (1), p.248-11, Article 248
• Main Authors: Luo, Na, Nixon, Mellissa J., Gonzalez-Ericsson, Paula I., Sanchez, Violeta, Opalenik, Susan R., Li, Huili, Zahnow, Cynthia A., Nickels, Michael L., Liu, Fei, Tantawy, Mohammed N., Sanders, Melinda E., Manning, H. Charles, Balko, Justin M.
• Format: Article
• Language: English
• Subjects: 13/51; 38/61; 45/77; 59/78; 631/67/1347; 692/4028/67/1347; 692/4028/67/580; 96/1; 96/106; 96/31; Animal models; Animals; Antigen presentation; Antineoplastic Agents - pharmacology; Azacitidine - analogs & derivatives; Azacitidine - pharmacology; Breast cancer; Breast Neoplasms - metabolism; Cancer; CD8 antigen; Cell Line, Tumor; Cytotoxicity; Deoxyribonucleic acid; DNA; DNA (Cytosine-5-)-Methyltransferase 1 - antagonists & inhibitors; DNA (Cytosine-5-)-Methyltransferase 1 - genetics; DNA (Cytosine-5-)-Methyltransferase 1 - metabolism; DNA methyltransferase; Female; Gene expression; Gene Expression Regulation, Enzymologic - drug effects; Gene Expression Regulation, Neoplastic - drug effects; Genes; Genes, MHC Class I - genetics; Genes, MHC Class I - physiology; Humanities and Social Sciences; Humans; Immunity; Immunomodulation; Inhibition; Interferon; Lymphocytes; Lymphocytes T; Major histocompatibility complex; Mammary Neoplasms, Experimental; Mice; multidisciplinary; Promoter Regions, Genetic; Science; Science (multidisciplinary); T-Lymphocytes, Cytotoxic - physiology; Tumor cell lines; Tumor cells
• ISSN: 2041-1723; 2041-1723
• 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. Immunotherapy often fails as a single option treatment in cancer. Here, the authors show that targeting of DNA methyltransferases, such as DNMT1, can potentiate anti-tumor immunity and response to checkpoint inhibition by increasing MHC gene expression and the recruitment of CD8+ T cells.