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
  • 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.

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