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Series GSE94057 Query DataSets for GSE94057
Status Public on Feb 01, 2017
Title BET-Bromodomain Inhibitors Engage The Host Immune System And Regulate Expression Of The Immune Checkpoint Ligand PD-L1 [3mRNA-seq]
Organisms Homo sapiens; Mus musculus
Experiment type Expression profiling by high throughput sequencing
Summary 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.
 
Overall design RNA Sequencing (3'-mRNA-Seq, QuantSeq) of AT3 (mouse mammary tumor cell line) and ALF1 (human plasma cell leukaemia line) treated for 2 hours with JQ1, interferon-gamma, JQ1+interferon-gamma, or DMSO vehicle.
 
Contributor(s) Hogg SJ, Vervoort SJ, Shortt J, Johnstone RW
Citation(s) 28249162
Submission date Jan 25, 2017
Last update date May 15, 2019
Contact name Simon J Hogg
Organization name AbbVie
Department Oncology Discovery Research
Street address 1000 Gateway Boulevard
City South San Francisco
State/province California
ZIP/Postal code 94080
Country USA
 
Platforms (2)
GPL16791 Illumina HiSeq 2500 (Homo sapiens)
GPL17021 Illumina HiSeq 2500 (Mus musculus)
Samples (16)
GSM2467642 SH-AT3-1 3'RNA-Seq
GSM2467643 SH-AT3-2 3'RNA-Seq
GSM2467644 SH-AT3-3 3'RNA-Seq
This SubSeries is part of SuperSeries:
GSE94134 BET-Bromodomain Inhibitors Engage The Host Immune System And Regulate Expression Of The Immune Checkpoint Ligand PD-L1
Relations
BioProject PRJNA368684
SRA SRP097749

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SOFT formatted family file(s) SOFTHelp
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Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE94057_Hogg_ALF1_3mRNAseq_countsmatrix.txt.gz 451.8 Kb (ftp)(http) TXT
GSE94057_Hogg_AT3_3mRNAseq_countsmatrix.txt.gz 314.5 Kb (ftp)(http) TXT
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Raw data are available in SRA
Processed data are available on Series record

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