1. Mutant IDH1 inhibition induces dsDNA sensing to activate tumor immunity.
- Author
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Wu MJ, Kondo H, Kammula AV, Shi L, Xiao Y, Dhiab S, Xu Q, Slater CJ, Avila OI, Merritt J, Kato H, Kattel P, Sussman J, Gritti I, Eccleston J, Sun Y, Cho HM, Olander K, Katsuda T, Shi DD, Savani MR, Smith BC, Cleary JM, Mostoslavsky R, Vijay V, Kitagawa Y, Wakimoto H, Jenkins RW, Yates KB, Paik J, Tassinari A, Saatcioglu DH, Tron AE, Haas W, Cahill D, McBrayer SK, Manguso RT, and Bardeesy N
- Subjects
- Animals, Humans, Mice, Cell Line, Tumor, DNA metabolism, DNA Demethylation, DNA Methylation, DNA Transposable Elements, Epigenesis, Genetic, Glutarates metabolism, Mutation, Nucleotidyltransferases genetics, Tumor Escape, Immunity, Innate genetics, Isocitrate Dehydrogenase genetics, Isocitrate Dehydrogenase metabolism, Neoplasms immunology, Neoplasms genetics, Immune Evasion genetics
- Abstract
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 antitumor immunity. Here, we define a cell-autonomous mechanism of mIDH1-driven immune evasion. IDH1 -mutant solid tumors show selective hypermethylation and silencing of the cytoplasmic double-stranded DNA (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 (TE-RT) activates cGAS, triggering viral mimicry and stimulating antitumor immunity. In summary, we demonstrate that mIDH1 epigenetically suppresses innate immunity and link endogenous RT activity to the mechanism of action of a US Food and Drug Administration-approved oncology drug.
- Published
- 2024
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