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BET Bromodomain Inhibition Promotes Anti-tumor Immunity by Suppressing PD-L1 Expression
Hengrui Zhu1, Fee Bengsch1, Nikolaos Svoronos2
1Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA 19104, USA.
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.
Insights
BET bromodomain inhibition suppresses PD-L1 expression, enhancing anti-tumor immunity in ovarian cancer. This small-molecule approach offers a potential new cancer therapy strategy by targeting PD-L1 signaling.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Immune checkpoint blockade, particularly targeting PD-L1 signaling, is a cornerstone of modern cancer therapy.
- BET bromodomain proteins, such as BRD4, play critical roles in gene transcription and are implicated in various cancers.
Purpose of the Study:
- To investigate the role of BET bromodomain inhibition in regulating PD-L1 expression in ovarian cancer.
- To evaluate the therapeutic potential of BET inhibitors in suppressing tumor progression by modulating anti-tumor immunity.
Main Methods:
- Utilized mouse models of ovarian cancer.
- Administered the BET inhibitor JQ1 to assess its effects on PD-L1 expression.
- Analyzed PD-L1 levels on tumor cells, dendritic cells, and macrophages.
- Evaluated the activity of anti-tumor cytotoxic T cells.
- Assessed tumor progression in response to BET inhibitor treatment.
Main Results:
- BET bromodomain inhibition, specifically with JQ1, significantly reduced PD-L1 (CD274) expression in ovarian tumors.
- PD-L1 is a direct transcriptional target of BRD4.
- JQ1 treatment led to increased cytotoxic T cell activity against tumors.
- BET inhibitor treatment effectively limited tumor progression in a manner dependent on cytotoxic T cells.
Conclusions:
- Pharmacological inhibition of BET bromodomains represents a viable small-molecule strategy to block PD-L1 signaling in cancer.
- BET inhibitors demonstrate potential as a novel therapeutic approach for ovarian cancer by restoring anti-tumor immunity.
- The established safety profile of BET inhibitors in clinical trials supports their consideration for PD-L1 targeted cancer therapy.
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