BioProject

Isocitrate Dehydrogenase 1 (IDH1) is the most commonly mutated metabolic gene across human cancers. More...

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: Immunocompetent mice harboring subcutaneous allograft tumors generated with murine CKIR132C ICC cells (2205-sgCtrl, -sgTet2) were treated (~100 mm^3 starting volume) with vehicle or AG120 (150 mg/kg; twice daily), and tumors were harvested at serial time points (Vehcle, AG120-Day3 and AG120-Day 6). sgCtrl and sgTet2 CKIR132C ICC cells were isolated by magnetic bead–mediated depletion of stromal populations from tumors treated with vehicle or AG120 for 3 or 6 days. Less...