2. Academic Validation
  3. Mutant IDH1 inhibition induces dsDNA sensing to activate tumor immunity

Mutant IDH1 inhibition induces dsDNA sensing to activate tumor immunity

  • Science. 2024 Jul 12;385(6705):eadl6173. doi: 10.1126/science.adl6173.
Meng-Ju Wu # 1 2 3 4,  Hiroshi Kondo # 1 2 3 4,  Ashwin V Kammula # 1 3 4,  Lei Shi 1 2 3 4,  Yi Xiao 5,  Sofiene Dhiab 1 2 3 4,  Qin Xu 1 2 3 4,  Chloe J Slater 1 2 3 6 7,  Omar I Avila 1 3 4,  Joshua Merritt 1 2 3 4,  Hiroyuki Kato 1 2 3 4,  Prabhat Kattel 1 2 3 4,  Jonathan Sussman 8 9,  Ilaria Gritti 1 2 3 4,  Jason Eccleston 8,  Yi Sun 1,  Hyo Min Cho 1 2 3 4,  Kira Olander 4,  Takeshi Katsuda 8,  Diana D Shi 5 10,  Milan R Savani 5 11,  Bailey C Smith 5,  James M Cleary,  Raul Mostoslavsky 1 2 3 4,  Vindhya Vijay 1 2 3 4,  Yosuke Kitagawa 12,  Hiroaki Wakimoto 12,  Russell W Jenkins 1 3 4 13,  Kathleen B Yates 1 3 4,  Jihye Paik 14,  Ania Tassinari 7,  Duygu Hatice Saatcioglu 7,  Adriana E Tron 7,  Wilhelm Haas 1 3,  Daniel Cahill 12,  Samuel K McBrayer 5 15,  Robert T Manguso 1 3 4,  Nabeel Bardeesy 1 2 3 4
Affiliations

Affiliations

  • 1 Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston MA, USA.
  • 2 Center for Regenerative Medicine, Massachusetts General Hospital, Boston MA, USA.
  • 3 Department of Medicine, Harvard Medical School, Boston, MA, USA.
  • 4 Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA.
  • 5 Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • 6 Universite Paris-Saclay, Institut Gustave Roussy, INSERM U1015, Villejuif, France.
  • 7 Servier Pharmaceuticals LLC, Boston, MA, USA.
  • 8 Abramson Family Cancer Research Institute and Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
  • 9 Graduate Group in Genomics and Computational Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
  • 10 Department of Radiation Oncology, Dana-Farber/Brigham and Women's Cancer Center, Harvard Medical School, Boston, MA, USA.
  • 11 Medical Scientist Training Program, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • 12 Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
  • 13 Laboratory of Systems Pharmacology, Harvard Program in Therapeutic Sciences, Harvard Medical School, Boston, MA, USA.
  • 14 Department of Pathology and Laboratory Medicine, Sandra and Edward Meyer Cancer Center, Weill Medical College of Cornell University, New York, NY, USA.
  • 15 Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • # Contributed equally.
PMID: 38991060 DOI: 10.1126/science.adl6173
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.

Figures
Products