Mutant IDH1 inhibition induces dsDNA sensing to activate tumor immunity.

Autor: Wu MJ; Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston MA, USA.; Center for Regenerative Medicine, Massachusetts General Hospital, Boston MA, USA.; Department of Medicine, Harvard Medical School, Boston, MA, USA.; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA., Kondo H; Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston MA, USA.; Center for Regenerative Medicine, Massachusetts General Hospital, Boston MA, USA.; Department of Medicine, Harvard Medical School, Boston, MA, USA.; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA., Kammula AV; Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston MA, USA.; Department of Medicine, Harvard Medical School, Boston, MA, USA.; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA., Shi L; Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston MA, USA.; Center for Regenerative Medicine, Massachusetts General Hospital, Boston MA, USA.; Department of Medicine, Harvard Medical School, Boston, MA, USA.; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA., Xiao Y; Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA., Dhiab S; Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston MA, USA.; Center for Regenerative Medicine, Massachusetts General Hospital, Boston MA, USA.; Department of Medicine, Harvard Medical School, Boston, MA, USA.; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA., Xu Q; Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston MA, USA.; Center for Regenerative Medicine, Massachusetts General Hospital, Boston MA, USA.; Department of Medicine, Harvard Medical School, Boston, MA, USA.; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA., Slater CJ; Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston MA, USA.; Center for Regenerative Medicine, Massachusetts General Hospital, Boston MA, USA.; Department of Medicine, Harvard Medical School, Boston, MA, USA.; Universite Paris-Saclay, Institut Gustave Roussy, INSERM U1015, Villejuif, France.; Servier Pharmaceuticals LLC, Boston, MA, USA., Avila OI; Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston MA, USA.; Department of Medicine, Harvard Medical School, Boston, MA, USA.; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA., Merritt J; Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston MA, USA.; Center for Regenerative Medicine, Massachusetts General Hospital, Boston MA, USA.; Department of Medicine, Harvard Medical School, Boston, MA, USA.; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA., Kato H; Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston MA, USA.; Center for Regenerative Medicine, Massachusetts General Hospital, Boston MA, USA.; Department of Medicine, Harvard Medical School, Boston, MA, USA.; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA., Kattel P; Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston MA, USA.; Center for Regenerative Medicine, Massachusetts General Hospital, Boston MA, USA.; Department of Medicine, Harvard Medical School, Boston, MA, USA.; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA., Sussman J; Abramson Family Cancer Research Institute and Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.; Graduate Group in Genomics and Computational Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA., Gritti I; Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston MA, USA.; Center for Regenerative Medicine, Massachusetts General Hospital, Boston MA, USA.; Department of Medicine, Harvard Medical School, Boston, MA, USA.; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA., Eccleston J; Abramson Family Cancer Research Institute and Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA., Sun Y; Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston MA, USA., Cho HM; Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston MA, USA.; Center for Regenerative Medicine, Massachusetts General Hospital, Boston MA, USA.; Department of Medicine, Harvard Medical School, Boston, MA, USA.; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA., Olander K; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA., Katsuda T; Abramson Family Cancer Research Institute and Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA., Shi DD; Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.; Department of Radiation Oncology, Dana-Farber/Brigham and Women's Cancer Center, Harvard Medical School, Boston, MA, USA., Savani MR; Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.; Medical Scientist Training Program, University of Texas Southwestern Medical Center, Dallas, TX, USA., Smith BC; Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA., Cleary JM, Mostoslavsky R; Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston MA, USA.; Center for Regenerative Medicine, Massachusetts General Hospital, Boston MA, USA.; Department of Medicine, Harvard Medical School, Boston, MA, USA.; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA., Vijay V; Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston MA, USA.; Center for Regenerative Medicine, Massachusetts General Hospital, Boston MA, USA.; Department of Medicine, Harvard Medical School, Boston, MA, USA.; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA., Kitagawa Y; Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA., Wakimoto H; Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA., Jenkins RW; Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston MA, USA.; Department of Medicine, Harvard Medical School, Boston, MA, USA.; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA.; Laboratory of Systems Pharmacology, Harvard Program in Therapeutic Sciences, Harvard Medical School, Boston, MA, USA., Yates KB; Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston MA, USA.; Department of Medicine, Harvard Medical School, Boston, MA, USA.; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA., Paik J; Department of Pathology and Laboratory Medicine, Sandra and Edward Meyer Cancer Center, Weill Medical College of Cornell University, New York, NY, USA., Tassinari A; Servier Pharmaceuticals LLC, Boston, MA, USA., Saatcioglu DH; Servier Pharmaceuticals LLC, Boston, MA, USA., Tron AE; Servier Pharmaceuticals LLC, Boston, MA, USA., Haas W; Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston MA, USA.; Department of Medicine, Harvard Medical School, Boston, MA, USA., Cahill D; Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA., McBrayer SK; Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.; Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA., Manguso RT; Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston MA, USA.; Department of Medicine, Harvard Medical School, Boston, MA, USA.; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA., Bardeesy N; Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston MA, USA.; Center for Regenerative Medicine, Massachusetts General Hospital, Boston MA, USA.; Department of Medicine, Harvard Medical School, Boston, MA, USA.; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA.
Jazyk: angličtina
Zdroj: Science (New York, N.Y.) [Science] 2024 Jul 12; Vol. 385 (6705), pp. eadl6173. Date of Electronic Publication: 2024 Jul 12.
DOI: 10.1126/science.adl6173
Abstrakt: 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.
Databáze: MEDLINE
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