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.
Hengrui Zhu  1 ,  Fee Bengsch  1 ,  Nikolaos Svoronos  2 ,  Melanie R Rutkowski  2 ,  Benjamin G Bitler  1 ,  Michael J Allegrezza  2 ,  Yuhki Yokoyama  1 ,  Andrew V Kossenkov  3 ,  James E Bradner  4 ,  Jose R Conejo-Garcia  5 ,  Rugang Zhang  6
Affiliations
  • 1. Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA 19104, USA.
  • 2. Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA.
  • 3. Center for Systems and Computational Biology, The Wistar Institute, Philadelphia, PA 19104, USA.
  • 4. Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
  • 5. Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA. Electronic address: [email protected].
  • 6. Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA 19104, USA. Electronic address: [email protected].
PMID: 27626654 DOI: 10.1016/j.celrep.2016.08.032
Abstract

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.