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Mutant IDH1 inhibition induces dsDNA sensing to activate tumor immunity.
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.
Afiliación
  • Wu MJ; Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston MA, USA.
  • Kondo H; Center for Regenerative Medicine, Massachusetts General Hospital, Boston MA, USA.
  • Kammula AV; Department of Medicine, Harvard Medical School, Boston, MA, USA.
  • Shi L; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA.
  • Xiao Y; Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston MA, USA.
  • Dhiab S; Center for Regenerative Medicine, Massachusetts General Hospital, Boston MA, USA.
  • Xu Q; Department of Medicine, Harvard Medical School, Boston, MA, USA.
  • Slater CJ; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA.
  • Avila OI; Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston MA, USA.
  • Merritt J; Department of Medicine, Harvard Medical School, Boston, MA, USA.
  • Kato H; 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.
  • Sussman J; Center for Regenerative Medicine, Massachusetts General Hospital, Boston MA, USA.
  • Gritti I; Department of Medicine, Harvard Medical School, Boston, MA, USA.
  • Eccleston J; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA.
  • Sun Y; Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Cho HM; Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston MA, USA.
  • Olander K; Center for Regenerative Medicine, Massachusetts General Hospital, Boston MA, USA.
  • Katsuda T; Department of Medicine, Harvard Medical School, Boston, MA, USA.
  • Shi DD; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA.
  • Savani MR; Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston MA, USA.
  • Smith BC; Center for Regenerative Medicine, Massachusetts General Hospital, Boston MA, USA.
  • Cleary JM; Department of Medicine, Harvard Medical School, Boston, MA, USA.
  • Mostoslavsky R; 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.
  • Kitagawa Y; Center for Regenerative Medicine, Massachusetts General Hospital, Boston MA, USA.
  • Wakimoto H; Department of Medicine, Harvard Medical School, Boston, MA, USA.
  • Jenkins RW; Universite Paris-Saclay, Institut Gustave Roussy, INSERM U1015, Villejuif, France.
  • Yates KB; Servier Pharmaceuticals LLC, Boston, MA, USA.
  • Paik J; Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston MA, USA.
  • Tassinari A; Department of Medicine, Harvard Medical School, Boston, MA, USA.
  • Saatcioglu DH; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA.
  • Tron AE; Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston MA, USA.
  • Haas W; Center for Regenerative Medicine, Massachusetts General Hospital, Boston MA, USA.
  • Cahill D; Department of Medicine, Harvard Medical School, Boston, MA, USA.
  • McBrayer SK; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA.
  • Manguso RT; Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston MA, USA.
  • Bardeesy N; Center for Regenerative Medicine, Massachusetts General Hospital, Boston MA, USA.
Science ; 385(6705): eadl6173, 2024 Jul 12.
Article en En | MEDLINE | ID: mdl-38991060
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.
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Evasión Inmune / Inmunidad Innata / Isocitrato Deshidrogenasa / Neoplasias Límite: Animals / Humans Idioma: En Revista: Science Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos
Texto completo
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Evasión Inmune / Inmunidad Innata / Isocitrato Deshidrogenasa / Neoplasias Límite: Animals / Humans Idioma: En Revista: Science Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos