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Series GSE265806 Query DataSets for GSE265806
Status Public on Apr 28, 2024
Title Mutant IDH1 inhibition induces dsDNA sensing to activate tumor immunity [mouse WGBS]
Organism Mus musculus
Experiment type Methylation profiling by high throughput sequencing
Summary Isocitrate Dehydrogenase 1 (IDH1) is the most commonly mutated metabolic gene across human cancers. Mutant IDH1 (mIDH1) generates the oncometabolite (R)-2-hydroxyglutarate, disrupting enzymes involved in epigenetics and other processes. A hallmark of IDH1-mutant solid tumors is T cell exclusion, whereas mIDH1 inhibition in preclinical models restores anti-tumor immunity. Here, we define a cell-autonomous mechanism of mIDH1-driven immune evasion. IDH1-mutant solid tumors show striking, selective hypermethylation and silencing of the cytoplasmic dsDNA sensor, CGAS, compromising innate immune signaling. mIDH1 inhibition restores DNA demethylation, derepressing CGAS and transposable element (TE) subclasses. dsDNA produced by TE-reverse transcriptase activates cGAS, triggering viral mimicry and stimulating anti-tumor immunity. Thus, we demonstrate that mIDH1 epigenetically suppresses innate immunity and link endogenous reverse transcriptase activity to the mechanism of action of an FDA-approved oncology drug.
Overall design This study used the mIDH inhibitor, AG120 (Servier Pharmaceuticals). Murine ICC (2205) cells were treated for five days with either DMSO or 1 μM mIDH inhibitor (AG120). Where indicated, 10ng/mL IFNγ was added for the final two days of culturing. Cells were collected for WGBS on the fifth day. The normal livers were from vehicle- or AG120-treated mice for 6 days.
Contributor(s) Wu MJ, Kammula AV, Manguso RT, Bardeesy N
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Submission date Apr 24, 2024
Last update date Apr 30, 2024
Contact name Robert Manguso
Organization name Broad Institute of MIT and Harvard
Street address 75 Ames Street
City Cambridge
State/province MA
ZIP/Postal code 02142
Country USA
Platforms (1)
GPL24247 Illumina NovaSeq 6000 (Mus musculus)
Samples (16)
GSM8229476 WGBS, 2205 in vitro, DMSO, Replicate 1
GSM8229477 WGBS, 2205 in vitro, DMSO, Replicate 2
GSM8229478 WGBS, 2205 in vitro, DMSO, Replicate 3
This SubSeries is part of SuperSeries:
GSE264730 Mutant IDH1 inhibition induces dsDNA sensing to activate tumor immunity
BioProject PRJNA1104239

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Supplementary file Size Download File type/resource
GSE265806_RAW.tar 3.6 Gb (http)(custom) TAR (of COV)
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Raw data are available in SRA

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