Journal article
BET-Bromodomain Inhibitors Engage the Host Immune System and Regulate Expression of the Immune Checkpoint Ligand PD-L1
SJ Hogg, SJ Vervoort, S Deswal, CJ Ott, J Li, LA Cluse, PA Beavis, PK Darcy, BP Martin, A Spencer, AK Traunbauer, I Sadovnik, K Bauer, P Valent, JE Bradner, J Zuber, J Shortt, RW Johnstone
Cell Reports | CELL PRESS | Published : 2017
Open access
Abstract
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 i..
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Grants
Awarded by Cancer Therapeutics Cooperative Research Centre
Funding Acknowledgements
This work was supported by research funding from the Leukaemia Foundation of Australia (S.J.H.), the Cancer Therapeutics CRC (S.J.H.), a Kids Cancer project grant (S.J.V.), a Rubicon Postdoctoral Fellowship (S.J.V.; NWO 019.161LW.017), the Eva and Les Erdi/Snowdome Foundation (J.S.,SNOW04), the Cancer Council Victoria (APP1081422), the National Health and Medical Research Council of Australia (NHMRC, APP1077867), the Victorian Cancer Agency, SFB project grants F4704 (P.V.) and F4710 (J.Z.) of the Austrian Science Fund (FWF), a Marie-Curie Fellowship of the European Union (S.D.) and a Starting Grant (ERC 336860) of the European Research Council (J.Z.). We thank members of the Johnstone lab, Garth Cameron and Dale Godfrey (Peter Doherty Institute, Australia) for helpful discussions, Prof. Mark Dawson and Dr. Chun Fong for reagents and advice, Dr. Anoop Kavirayani (VBCF, Austria) for histology support, Prof. Maher Gandhi (UoQ Diamantina Institute, Australia) for L540 cells, Prof. Huey-Kang Sytwu (National Defense Medical Center, Taipei) for murine Pd-l1 cDNA, and Dr. Ross Dickins (Monash University, Australia) for Myc shRNAs. The Dana-Farber Cancer Institute has licensed intellectual property from the Bradner Laboratory concerning BET bromodomain inhibitors to Tensha Therapeutics, now owned by Roche Pharmaceuticals. The Johnstone Laboratory receives funding to conduct studies associated with JQ1.