Mutant IDH1 inhibition induces dsDNA sensing to activate tumor immunity

doi:10.1126/science.adl6173

. 2024 Jul 12;385(6705):eadl6173.

doi: 10.1126/science.adl6173. Epub 2024 Jul 12.

Mutant IDH1 inhibition induces dsDNA sensing to activate tumor immunity

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 Xiao⁵, 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 Eccleston⁸, Yi Sun¹, Hyo Min Cho^{1

2

3

4}, Kira Olander⁴, Takeshi Katsuda⁸, Diana D Shi^{5

10}, Milan R Savani^{5

11}, Bailey C Smith⁵, James M Cleary, Raul Mostoslavsky^{1

2

3

4}, Vindhya Vijay^{1

2

3

4}, Yosuke Kitagawa¹², Hiroaki Wakimoto¹², Russell W Jenkins^{1

3

4

13}, Kathleen B Yates^{1

3

4}, Jihye Paik¹⁴, Ania Tassinari⁷, Duygu Hatice Saatcioglu⁷, Adriana E Tron⁷, Wilhelm Haas^{1

3}, Daniel Cahill¹², 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

Mutant IDH1 inhibition induces dsDNA sensing to activate tumor immunity

Meng-Ju Wu et al. Science. 2024.

. 2024 Jul 12;385(6705):eadl6173.

doi: 10.1126/science.adl6173. Epub 2024 Jul 12.

Authors

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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Comment in

Unmasking immune suppression.
Pitarresi JR, Fitzgerald KA. Pitarresi JR, et al. Science. 2024 Jul 12;385(6705):140-142. doi: 10.1126/science.adq5196. Epub 2024 Jul 11. Science. 2024. PMID: 38991086

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Mutant IDH1 inhibition induces dsDNA sensing to activate tumor immunity

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Mutant IDH1 inhibition induces dsDNA sensing to activate tumor immunity

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