Journal
NATURE COMMUNICATIONS
Volume 9, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-017-02630-w
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Funding
- V Foundation for Cancer Research [V2016-012]
- China Scholarship Council [201406205050]
- NIH/NCI [R00CA181491]
- Susan G. Komen for the Cure Foundation [CCR14299052]
- Breast Cancer Specialized Program of Research Excellence (SPORE) [P50 CA098131]
- Vanderbilt-Ingram Cancer Center Support Grant [P30 CA68485]
- Kleburg Foundation
- Trans-Institutional Programs (TIPS) award
- Vanderbilt University Office of Research support of the Radiochemistry Core Resource
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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-gamma 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.
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