BET Bromodomain Inhibition Promotes Anti-tumor Immunity by Suppressing PD-L1 Expression.
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.
Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA 19104, USA.
Hengrui
H
Zhu
Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA 19104, USA.
Fee
F
Bengsch
Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA.
Nikolaos
N
Svoronos
Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA.
Melanie R
MR
Rutkowski
Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA 19104, USA.
Benjamin G
BG
Bitler
Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA.
Michael J
MJ
Allegrezza
Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA 19104, USA.
Yuhki
Y
Yokoyama
Center for Systems and Computational Biology, The Wistar Institute, Philadelphia, PA 19104, USA.
Andrew V
AV
Kossenkov
Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
James E
JE
Bradner
Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA. Electronic address: jrconejo@wistar.org.
Jose R
JR
Conejo-Garcia
Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA 19104, USA. Electronic address: rzhang@wistar.org.
Rugang
R
Zhang
D000818:Animals; D001381:Azepines / Q000494:pharmacology*; D060890:B7-H1 Antigen / Q000235:genetics* / Q000378:metabolism; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D018450:Disease Progression; D005260:Female; D006801:Humans; D007109:Immunity / Q000187:drug effects*; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D009687:Nuclear Proteins / Q000378:metabolism; D011506:Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D014230:Triazoles / Q000494:pharmacology*; D000092468:Bromodomain Containing Proteins
D001381:Azepines; D060890:B7-H1 Antigen; D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D011506:Proteins; D014157:Transcription Factors; D014230:Triazoles; C561695:(+)-JQ1 compound; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C000624329:bromodomain and extra-terminal domain protein, human