title: BET-Bromodomain Inhibitors Engage the Host Immune System and Regulate Expression of the Immune Checkpoint Ligand PD-L1.
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 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.
authors.affiliation: Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia.
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Hogg
authors.affiliation: Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia.
authors.forename: Stephin J
authors.initials: SJ
authors.lastname: Vervoort
authors.affiliation: Research Institute of Molecular Pathology (IMP), Vienna Biocenter (VBC), 1030 Vienna, Austria.
authors.forename: Sumit
authors.initials: S
authors.lastname: Deswal
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Ott
authors.affiliation: Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia.
authors.forename: Jason
authors.initials: J
authors.lastname: Li
authors.affiliation: Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia.
authors.forename: Leonie A
authors.initials: LA
authors.lastname: Cluse
authors.affiliation: Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Beavis
authors.affiliation: Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia.
authors.forename: Phillip K
authors.initials: PK
authors.lastname: Darcy
authors.affiliation: Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia.
authors.forename: Benjamin P
authors.initials: BP
authors.lastname: Martin
authors.affiliation: Australian Center for Blood Diseases, Monash University, Melbourne, VIC 3004, Australia.
authors.forename: Andrew
authors.initials: A
authors.lastname: Spencer
authors.affiliation: Research Institute of Molecular Pathology (IMP), Vienna Biocenter (VBC), 1030 Vienna, Austria.
authors.forename: Anna K
authors.initials: AK
authors.lastname: Traunbauer
authors.affiliation: Division of Hematology and Hemostaseology, Department of Internal Medicine, Medical University of Vienna, 1090 Wien, Austria.
authors.forename: Irina
authors.initials: I
authors.lastname: Sadovnik
authors.affiliation: Division of Hematology and Hemostaseology, Department of Internal Medicine, Medical University of Vienna, 1090 Wien, Austria; Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, 1090 Wien, Austria.
authors.forename: Karin
authors.initials: K
authors.lastname: Bauer
authors.affiliation: Division of Hematology and Hemostaseology, Department of Internal Medicine, Medical University of Vienna, 1090 Wien, Austria; Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, 1090 Wien, Austria.
authors.forename: Peter
authors.initials: P
authors.lastname: Valent
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: James E
authors.initials: JE
authors.lastname: Bradner
authors.affiliation: Research Institute of Molecular Pathology (IMP), Vienna Biocenter (VBC), 1030 Vienna, Austria.
authors.forename: Johannes
authors.initials: J
authors.lastname: Zuber
authors.affiliation: Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia; Monash Haematology, Monash Health, Clayton, VIC 3168, Australia; School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC 3168, Australia. Electronic address: jake.shortt@monashhealth.org.
authors.forename: Jake
authors.initials: J
authors.lastname: Shortt
authors.affiliation: Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia. Electronic address: ricky.johnstone@petermac.org.
authors.forename: Ricky W
authors.initials: RW
authors.lastname: Johnstone
mesh_terms: D000818:Animals; D060890:B7-H1 Antigen / Q000276:immunology; D045744:Cell Line, Tumor; D015252:Deoxyribonucleases, Type II Site-Specific / Q000276:immunology*; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology; D006801:Humans; D007107:Immune System / Q000276:immunology*; D007371:Interferon-gamma / Q000276:immunology; D008024:Ligands; D016393:Lymphoma, B-Cell / Q000276:immunology; D051379:Mice; D009687:Nuclear Proteins / Q000276:immunology*; D061026:Programmed Cell Death 1 Receptor / Q000276:immunology*; D016271:Proto-Oncogene Proteins c-myc / Q000276:immunology; D012333:RNA, Messenger / Q000276:immunology; D014157:Transcription Factors / Q000276:immunology*; D014158:Transcription, Genetic / Q000276:immunology
chemical_list: D060890:B7-H1 Antigen; D008024:Ligands; D009687:Nuclear Proteins; D061026:Programmed Cell Death 1 Receptor; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D014157:Transcription Factors; D007371:Interferon-gamma; D015252:Deoxyribonucleases, Type II Site-Specific; C075961:WCCGGW-specific type II deoxyribonucleases
keywords: BRD4; PD-L1; bromodomain inhibitor; immune checkpoint