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

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

Author information

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: jrconejo@wistar.org.
6
Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA 19104, USA. Electronic address: rzhang@wistar.org.

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.

PMID:
27626654
PMCID:
PMC5177024
DOI:
10.1016/j.celrep.2016.08.032
[Indexed for MEDLINE]
Free PMC Article

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