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BET Bromodomain Inhibition Promotes Anti-tumor Immunity by Suppressing PD-L1 Expression
Open accessAbstract
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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“Meanwhile, treatment with JQ1-α specific inhibitor of the histone acetylation reader bromodomain-containing protein 4 (BRD4)results in decreased PD-L1 expression on tumor cells and macrophages, which is correlated with an increase in antitumor T cell activity (Zhu et al., 2016).”
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Metadata
- Authors
- Zhu, H., Bengsch, F., Svoronos, N., Rutkowski, M. R., Bitler, B. G., Allegrezza, M. J., Yokoyama, Y., Kossenkov, A. V., Bradner, J. E., Conejo-Garcia, J. R., & Zhang, R.
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2016-09
- Volume
- 16
- Issue
- 11
- Pages
- 2829-2837
- ISSN
- 2211-1247 (ISSN-L)
- OpenAlex
- W2520148131
- Cited by
- 432
- References
- 24
- FWCI
- 15.80
- Type
- journal article
- Language
- en
- Open access
- gold
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- creativecommons.org/licenses/by-nc-nd/4.0/ (vor)
- Funders
- NIH/National Cancer Institute (CA160331, CA163377, CA202919, K99CA194318)
- U.S. Department of Defense (OC140632P1, OC150446)
- Jayne Koskinas & Ted Giovanis Breast Cancer Research Consortium
- Cancer Center Support Grant (CA010815)
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