Mutant IDH1 inhibition induces dsDNA sensing to activate tumor immunity

• 成果类型: Article
• 署名作者: Wu, Meng-Ju; Kondo, Hiroshi; Kammula, Ashwin V.; Shi, Lei; Xiao, Yi; Dhiab, Sofiene; Xu, Qin; Slater, Chloe J.; Avila, Omar I.; Merritt, Joshua; Kato, Hiroyuki; Kattel, Prabhat; Sussman, Jonathan; Gritti, Ilaria; Eccleston, Jason; Sun, Yi; Cho, Hyo Min; Olander, Kira; Katsuda, Takeshi; Shi, Diana D.; Savani, Milan R.; Smith, Bailey C.; Cleary, James M.; Mostoslavsky, Raul; Vijay, Vindhya; Kitagawa, Yosuke; Wakimoto, Hiroaki; Jenkins, Russell W.; Yates, Kathleen B.; Paik, Jihye; Tassinari, Ania; Saatcioglu, Duygu Hatice; Tron, Adriana E.; Haas, Wilhelm; Cahill, Daniel; Mcbrayer, Samuel K.; Manguso, Robert T.; Bardeesy, Nabeel
• 署名单位: Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Harvard Medical School; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; University of Texas System; University of Texas Southwestern Medical Center; Institut National de la Sante et de la Recherche Medicale (Inserm); UNICANCER; Gustave Roussy; Universite Paris Saclay; University of Pennsylvania; University of Pennsylvania; University of Pennsylvania; Harvard University; Harvard Medical School; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; University of Texas System; University of Texas Southwestern Medical Center; Harvard University; Harvard Medical School; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard Medical School; Harvard University; Harvard Medical School; Cornell University; Weill Cornell Medicine; University of Texas System; University of Texas Southwestern Medical Center
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-9379
• DOI: 10.1126/science.adl6173
• 发表日期: 2024-07-12
• 关键词: differential expression analysis; reverse-transcriptase; endogenous retroviruses; transposable elements; cell-line; mutations; cancer; (r)-2-hydroxyglutarate; identification; maintenance

摘要

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.