BET-Bromodomain Inhibitors Engage The Host Immune System And Regulate Expression Of The Immune Checkpoint Ligand PD-L1
Ontology highlight
ABSTRACT:
OTHER RELATED OMICS DATASETS IN: PRJNA368684PRJNA369041PRJNA369031PRJNA369036
ORGANISM(S): Mus musculus Homo sapiens
PROVIDER: GSE94134 | GEO | 2017/02/01
SECONDARY ACCESSION(S): PRJNA369036
REPOSITORIES: GEO
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Project description: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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Project description:BET inhibitors (BETi) target bromodomain-containing proteins and are currently being evaluated as anti-cancer agents. We discovered that the 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 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 PD1/PD-L1 axis by combining anti-PD1 antibodies and the BETi JQ1 caused synergistic responses in mice bearing Myc-driven lymphomas. Our data uncovers a novel interaction between BETi and the PD-1/PD-L1 immune-checkpoint and provides novel insight into the transcriptional regulation of CD274.
2017-02-01 | GSE94057 | GEO
Project description:BET inhibitors (BETi) target bromodomain-containing proteins and are currently being evaluated as anti-cancer agents. We discovered that the 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 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 PD1/PD-L1 axis by combining anti-PD1 antibodies and the BETi JQ1 caused synergistic responses in mice bearing Myc-driven lymphomas. Our data uncovers a novel interaction between BETi and the PD-1/PD-L1 immune-checkpoint and provides novel insight into the transcriptional regulation of CD274.
2017-02-01 | GSE94133 | GEO
Project description:BET inhibitors (BETi) target bromodomain-containing proteins and are currently being evaluated as anti-cancer agents. We discovered that the 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 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 PD1/PD-L1 axis by combining anti-PD1 antibodies and the BETi JQ1 caused synergistic responses in mice bearing Myc-driven lymphomas. Our data uncovers a novel interaction between BETi and the PD-1/PD-L1 immune-checkpoint and provides novel insight into the transcriptional regulation of CD274.
2017-02-01 | GSE94130 | GEO
Project description:BET-Bromodomain Inhibitors Engage The Host Immune System And Regulate Expression Of The Immune Checkpoint Ligand PD-L1
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Project description:BET-Bromodomain Inhibitors Engage The Host Immune System And Regulate Expression Of The Immune Checkpoint Ligand PD-L1 [3mRNA-seq]
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