Journal
CELL REPORTS
Volume 16, Issue 11, Pages 2829-2837Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2016.08.032
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Funding
- NIH/National Cancer Institute [CA160331, CA163377, CA202919, K99CA194318]
- U.S. Department of Defense [OC140632P1, OC150446]
- Ovarian Cancer Research Fund (OCRF) program project
- Jayne Koskinas & Ted Giovanis Breast Cancer Research Consortium at Wistar
- Cancer Center Support Grant (CCSG) [CA010815]
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Restoration of anti-tumor immunity by blocking PD-L1 signaling through the use of antibodies has proven to be beneficial in cancer therapy. Here, we show that BET bromodomain inhibition suppresses PD-L1 expression and limits tumor progression in ovarian cancer. CD274 (encoding PD-L1) is a direct target of BRD4-mediated gene transcription. In mouse models, treatment with the BET inhibitor JQ1 significantly reduced PD-L1 expression on tumor cells and tumor-associated dendritic cells and macrophages, which correlated with an increase in the activity of anti-tumor cytotoxic T cells. The BET inhibitor limited tumor progression in a cytotoxic T-cell-dependent manner. Together, these data demonstrate a small-molecule approach to block PD-L1 signaling. Given the fact that BET inhibitors have been proven to be safe with manageable reversible toxicity in clinical trials, our findings indicate that pharmacological BET inhibitors represent a treatment strategy for targeting PD-L1 expression.
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