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

Cell Rep. 2016 Sep 13;16(11):2829-2837. doi: 10.1016/j.celrep.2016.08.032.


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.

MeSH terms

  • Animals
  • Azepines / pharmacology*
  • B7-H1 Antigen / genetics*
  • B7-H1 Antigen / metabolism
  • Cell Cycle Proteins
  • Cell Line, Tumor
  • Disease Progression
  • Female
  • Humans
  • Immunity / drug effects*
  • Mice, Inbred C57BL
  • Neoplasms / immunology*
  • Neoplasms / metabolism*
  • Neoplasms / pathology
  • Nuclear Proteins / metabolism
  • Proteins / antagonists & inhibitors*
  • Proteins / metabolism
  • T-Lymphocytes, Cytotoxic / drug effects
  • Time Factors
  • Transcription Factors / metabolism
  • Transcription, Genetic / drug effects
  • Triazoles / pharmacology*


  • (+)-JQ1 compound
  • Azepines
  • B7-H1 Antigen
  • BRD4 protein, human
  • Cell Cycle Proteins
  • Nuclear Proteins
  • Proteins
  • Transcription Factors
  • Triazoles
  • bromodomain and extra-terminal domain protein, human