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

Publication ,  Journal Article
Zhu, H; Bengsch, F; Svoronos, N; Rutkowski, MR; Bitler, BG; Allegrezza, MJ; Yokoyama, Y; Kossenkov, AV; Bradner, JE; Conejo-Garcia, JR; Zhang, R
Published in: Cell Rep
September 13, 2016

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.

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Published In

Cell Rep

DOI

EISSN

2211-1247

Publication Date

September 13, 2016

Volume

16

Issue

11

Start / End Page

2829 / 2837

Location

United States

Related Subject Headings

  • Triazoles
  • Transcription, Genetic
  • Transcription Factors
  • Time Factors
  • T-Lymphocytes, Cytotoxic
  • Proteins
  • Nuclear Proteins
  • Neoplasms
  • Mice, Inbred C57BL
  • Immunity
 

Citation

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Zhu, H., Bengsch, F., Svoronos, N., Rutkowski, M. R., Bitler, B. G., Allegrezza, M. J., … Zhang, R. (2016). BET Bromodomain Inhibition Promotes Anti-tumor Immunity by Suppressing PD-L1 Expression. Cell Rep, 16(11), 2829–2837. https://doi.org/10.1016/j.celrep.2016.08.032
Zhu, Hengrui, Fee Bengsch, Nikolaos Svoronos, Melanie R. Rutkowski, Benjamin G. Bitler, Michael J. Allegrezza, Yuhki Yokoyama, et al. “BET Bromodomain Inhibition Promotes Anti-tumor Immunity by Suppressing PD-L1 Expression.Cell Rep 16, no. 11 (September 13, 2016): 2829–37. https://doi.org/10.1016/j.celrep.2016.08.032.
Zhu H, Bengsch F, Svoronos N, Rutkowski MR, Bitler BG, Allegrezza MJ, et al. BET Bromodomain Inhibition Promotes Anti-tumor Immunity by Suppressing PD-L1 Expression. Cell Rep. 2016 Sep 13;16(11):2829–37.
Zhu, Hengrui, et al. “BET Bromodomain Inhibition Promotes Anti-tumor Immunity by Suppressing PD-L1 Expression.Cell Rep, vol. 16, no. 11, Sept. 2016, pp. 2829–37. Pubmed, doi:10.1016/j.celrep.2016.08.032.
Zhu H, Bengsch F, Svoronos N, Rutkowski MR, Bitler BG, Allegrezza MJ, Yokoyama Y, Kossenkov AV, Bradner JE, Conejo-Garcia JR, Zhang R. BET Bromodomain Inhibition Promotes Anti-tumor Immunity by Suppressing PD-L1 Expression. Cell Rep. 2016 Sep 13;16(11):2829–2837.
Journal cover image

Published In

Cell Rep

DOI

EISSN

2211-1247

Publication Date

September 13, 2016

Volume

16

Issue

11

Start / End Page

2829 / 2837

Location

United States

Related Subject Headings

  • Triazoles
  • Transcription, Genetic
  • Transcription Factors
  • Time Factors
  • T-Lymphocytes, Cytotoxic
  • Proteins
  • Nuclear Proteins
  • Neoplasms
  • Mice, Inbred C57BL
  • Immunity