BET-Bromodomain Inhibitors Engage the Host Immune System and Regulate Expression of the Immune Checkpoint Ligand PD-L1
Open accessAbstract
BET inhibitors (BETi) target bromodomain-containing proteins and are currently being evaluated as anti-cancer agents. We find that maximal therapeutic effects of BETi in a Myc-driven B cell lymphoma model required an intact host immune system. Genome-wide analysis of the BETi-induced transcriptional response identified the immune checkpoint ligand Cd274 (Pd-l1) as a Myc-independent, BETi target-gene. BETi directly repressed constitutively expressed and interferon-gamma (IFN-γ) induced CD274 expression across different human and mouse tumor cell lines and primary patient samples. Mechanistically, BETi decreased Brd4 occupancy at the Cd274 locus without any change in Myc occupancy, resulting in transcriptional pausing and rapid loss of Cd274 mRNA production. Finally, targeted inhibition of the PD-1/PD-L1 axis by combining anti-PD-1 antibodies and the BETi JQ1 caused synergistic responses in mice bearing Myc-driven lymphomas. Our data uncover an interaction between BETi and the PD-1/PD-L1 immune-checkpoint and provide mechanistic insight into the transcriptional regulation of CD274.
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Among the eight genes whose perturbation shifted PD-L1 protein levels, five were positive regulators (PD-L1 downregulation upon perturbation) and three were negative regulators.
“We identified five positive regulators (PD-L1 downregulation upon perturbation) and three negative regulators, a subset of which had been previously validated [9,11,13,16,17,29].”
From Characterizing the molecular regulation of inhibitory immune checkpoints with multimodal single-cell screens (2021) · cites this paper as [13]
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- Authors
- Hogg, S. J., Vervoort, S. J., Deswal, S., Ott, C. J., Li, J., Cluse, L. A., Beavis, P. A., Darcy, P. K., Martin, B. P., Spencer, A., Traunbauer, A. K., Sadovnik, I., Bauer, K., Valent, P., Bradner, J. E., Zuber, J., Shortt, J., & Johnstone, R. W.
- Affiliations
- The University of Melbourne (AU)
- Peter MacCallum Cancer Centre (AU)
- Research Institute of Molecular Pathology (AT)
- Dana-Farber Cancer Institute (US)
- Monash University (AU)
- Medical University of Vienna (AT)
- Ludwig Boltzmann Institute for Hematology and Oncology (AT)
- Corresponding author
- Shortt, Jake
- Johnstone, Ricky W.
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2017-02
- Volume
- 18
- Issue
- 9
- Pages
- 2162-2174
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC5340981
- OpenAlex
- W2592983486
- Cited by
- 308
- References
- 5
- Citations by year
- 2026: 21 · 2025: 26 · 2024: 28 · 2023: 33 · 2022: 41 · 2021: 49 · 2020: 34 · 2019: 39 · 2018: 22 · 2017: 13 · 2012: 1
- FWCI
- 12.18
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Monash University Research Portal (Monash University) (submittedVersion, cc-by-nc-nd)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- European Commission
- Monash University
- Austrian Science Fund (F4710)
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek (019.161LW.017)
- Cancer Therapeutics Cooperative Research Centre
- Medical Research Council
- National Health and Medical Research Council (1077867)
- Cancer Council Victoria
- Diamantina Institute, University of Queensland
- FP7 Ideas: European Research Council (336860)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- BET inhibitors, bromodomain proteins, BRD4, PD-L1, PD-1/PD-L1 axis, immune checkpoint, host immune system, transcriptional repression, interferon-gamma, JQ1, transcriptional pausing, epigenetic regulation
- MeSH terms
- Animals, Humans, Immune System, Interferon-gamma, Ligands, Nuclear Proteins, RNA, Messenger, Transcription Factors, Transcription, Genetic, Deoxyribonucleases, Type II Site-Specific, Gene Expression Regulation, Neoplastic, Proto-Oncogene Proteins c-myc, Lymphoma, B-Cell, Cell Line, Tumor, Mice, B7-H1 Antigen, Programmed Cell Death 1 Receptor
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