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

Research output: Research - peer-reviewArticle

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.

LanguageEnglish
Pages2162-2174
Number of pages13
JournalCell Reports
Volume18
Issue number9
DOIs
StatePublished - 28 Feb 2017

Keywords

  • BRD4
  • bromodomain inhibitor
  • immune checkpoint
  • PD-L1

Cite this

Hogg, S. J., Vervoort, S. J., Deswal, S., Ott, C. J., Li, J., Cluse, L. A., ... Johnstone, R. W. (2017). BET-Bromodomain Inhibitors Engage the Host Immune System and Regulate Expression of the Immune Checkpoint Ligand PD-L1. Cell Reports, 18(9), 2162-2174. DOI: 10.1016/j.celrep.2017.02.011
Hogg, Simon J. ; Vervoort, Stephin J. ; Deswal, Sumit ; Ott, Christopher J. ; Li, Jason ; Cluse, Leonie A. ; Beavis, Paul A. ; Darcy, Phillip K. ; Martin, Benjamin P. ; Spencer, Andrew ; Traunbauer, Anna K. ; Sadovnik, Irina ; Bauer, Karin ; Valent, Peter ; Bradner, James E. ; Zuber, Johannes ; Shortt, Jake ; Johnstone, Ricky W./ BET-Bromodomain Inhibitors Engage the Host Immune System and Regulate Expression of the Immune Checkpoint Ligand PD-L1. In: Cell Reports. 2017 ; Vol. 18, No. 9. pp. 2162-2174
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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.",
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Hogg, SJ, Vervoort, SJ, Deswal, S, Ott, CJ, Li, J, Cluse, LA, Beavis, PA, Darcy, PK, Martin, BP, Spencer, A, Traunbauer, AK, Sadovnik, I, Bauer, K, Valent, P, Bradner, JE, Zuber, J, Shortt, J & Johnstone, RW 2017, 'BET-Bromodomain Inhibitors Engage the Host Immune System and Regulate Expression of the Immune Checkpoint Ligand PD-L1' Cell Reports, vol 18, no. 9, pp. 2162-2174. DOI: 10.1016/j.celrep.2017.02.011

BET-Bromodomain Inhibitors Engage the Host Immune System and Regulate Expression of the Immune Checkpoint Ligand PD-L1. / Hogg, Simon J.; Vervoort, Stephin J.; Deswal, Sumit; Ott, Christopher J.; Li, Jason; Cluse, Leonie A.; Beavis, Paul A.; Darcy, Phillip K.; Martin, Benjamin P.; Spencer, Andrew; Traunbauer, Anna K.; Sadovnik, Irina; Bauer, Karin; Valent, Peter; Bradner, James E.; Zuber, Johannes; Shortt, Jake; Johnstone, Ricky W.

In: Cell Reports, Vol. 18, No. 9, 28.02.2017, p. 2162-2174.

Research output: Research - peer-reviewArticle

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AU - Hogg,Simon J.

AU - Vervoort,Stephin J.

AU - Deswal,Sumit

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AU - Li,Jason

AU - Cluse,Leonie A.

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AU - Darcy,Phillip K.

AU - Martin,Benjamin P.

AU - Spencer,Andrew

AU - Traunbauer,Anna K.

AU - Sadovnik,Irina

AU - Bauer,Karin

AU - Valent,Peter

AU - Bradner,James E.

AU - Zuber,Johannes

AU - Shortt,Jake

AU - Johnstone,Ricky W.

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AB - 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.

KW - BRD4

KW - bromodomain inhibitor

KW - immune checkpoint

KW - PD-L1

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Hogg SJ, Vervoort SJ, Deswal S, Ott CJ, Li J, Cluse LA et al. BET-Bromodomain Inhibitors Engage the Host Immune System and Regulate Expression of the Immune Checkpoint Ligand PD-L1. Cell Reports. 2017 Feb 28;18(9):2162-2174. Available from, DOI: 10.1016/j.celrep.2017.02.011