BET-Bromodomain Inhibitors Engage the Host Immune System and Regulate Expression of the Immune Checkpoint Ligand PD-L1
Simon J. Hogg,
Stephin J. Vervoort,
Sumit Deswal,
Christopher J. Ott,
Jason Li,
Leonie A. Cluse,
Paul A. Beavis,
Phillip K. Darcy,
Benjamin P. Martin,
Andrew Spencer,
Anna K. Traunbauer,
Irina Sadovnik,
Karin Bauer,
Peter Valent,
James E. Bradner,
Johannes Zuber,
Jake Shortt,
Ricky W. Johnstone
Affiliations
Simon J. Hogg
Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia
Stephin J. Vervoort
Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia
Sumit Deswal
Research Institute of Molecular Pathology (IMP), Vienna Biocenter (VBC), 1030 Vienna, Austria
Christopher J. Ott
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
Jason Li
Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia
Leonie A. Cluse
Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia
Paul A. Beavis
Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia
Phillip K. Darcy
Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia
Benjamin P. Martin
Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia
Andrew Spencer
Australian Center for Blood Diseases, Monash University, Melbourne, VIC 3004, Australia
Anna K. Traunbauer
Research Institute of Molecular Pathology (IMP), Vienna Biocenter (VBC), 1030 Vienna, Austria
Irina Sadovnik
Division of Hematology and Hemostaseology, Department of Internal Medicine, Medical University of Vienna, 1090 Wien, Austria
Karin Bauer
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
Peter Valent
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
James E. Bradner
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
Johannes Zuber
Research Institute of Molecular Pathology (IMP), Vienna Biocenter (VBC), 1030 Vienna, Austria
Jake Shortt
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; Corresponding author
Ricky W. Johnstone
Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia; Corresponding author
Summary: 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. : Hogg et al. find that BET bromodomain inhibitors promote anti-tumor immune responses through transcriptional repression of immune checkpoint ligand PD-L1 in genetically diverse tumor models and in response to inflammatory stimuli. Moreover, BET inhibitors enhance the efficacy of immune modulating therapies, such as checkpoint blockade. Keywords: bromodomain inhibitor, PD-L1, immune checkpoint, BRD4