BET Bromodomain Inhibition Promotes Anti-tumor Immunity by Suppressing PD-L1 Expression

• DOI: 10.1016/j.celrep.2016.08.032
• Publication Date: 2016-09-13T20:32:08Z
• Authors: Hengrui Zhu; Fee Bengsch; Nikolaos Svoronos; Melanie R. Rutkowski; Benjamin G. Bitler; Michael J. Allegr...; Yuhki Yokoyama; Andrew V. Kossenkov; James E. Bradner; Jose R. Conejo-Ga...; Rugang Zhang
• Keywords: 0301 basic medicine; Time Factors; Transcription, Genetic; QH301-705.5; Immunity; Nuclear Proteins; Proteins; Cell Cycle Proteins; Azepines; Triazoles; B7-H1 Antigen; 3. Good health; Mice, Inbred C57BL; 03 medical and health sciences; Cell Line, Tumor; Neoplasms; Disease Progression; Animals; Humans; Female; Biology (General); T-Lymphocytes, Cytotoxic; Transcription Factors

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.