Dryad
Published April 30, 2024 | Version v1
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Mutant IDH1 inhibition induces dsDNA sensing to activate tumor immunity

Authors/Creators

  • 1. Massachusetts General Hospital
  • 2. Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania
  • 3. Dana-Farber Cancer Institute
  • 4. The University of Texas Southwestern Medical Center
  • 5. Servier Pharmaceuticals LLC*
  • 6. Broad Institute
  • 7. Weill Cornell Medicine

Description

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 anti-tumor immunity. Here, we define a cell-autonomous mechanism of mIDH1-driven immune evasion. IDH1-mutant solid tumors show striking, selective hypermethylation and silencing of the cytoplasmic 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 activates cGAS, triggering viral mimicry and stimulating anti-tumor immunity. Thus, we demonstrate that mIDH1 epigenetically suppresses innate immunity and link endogenous reverse transcriptase activity to the mechanism of action of an FDA-approved oncology drug.

Notes

Funding provided by: American Cancer Society
ROR ID: https://ror.org/02e463172
Award Number: PF-20-136-01-TBG

Funding provided by: National Cancer Institute
ROR ID: https://ror.org/040gcmg81
Award Number: P50CA127003

Funding provided by: National Cancer Institute
ROR ID: https://ror.org/040gcmg81
Award Number: 1R01CA280085-01A1

Funding provided by: National Cancer Institute
ROR ID: https://ror.org/040gcmg81
Award Number: R01CA219670

Funding provided by: National Cancer Institute
ROR ID: https://ror.org/040gcmg81
Award Number: R01CA215498

Funding provided by: National Cancer Institute
ROR ID: https://ror.org/040gcmg81
Award Number: P01CA117969

Funding provided by: National Cancer Institute
ROR ID: https://ror.org/040gcmg81
Award Number: K99CA277576

Funding provided by: National Cancer Institute
ROR ID: https://ror.org/040gcmg81
Award Number: K12CA0903354

Funding provided by: National Cancer Institute
ROR ID: https://ror.org/040gcmg81
Award Number: F30CA271634

Funding provided by: TargetCancer Foundation
ROR ID: https://ror.org/02hk1y795
Award Number:

Funding provided by: Massachusetts Life Sciences Center
ROR ID: https://ror.org/033km2469
Award Number:

Funding provided by: Cholangiocarcinoma Foundation
ROR ID: https://ror.org/04fp9z389
Award Number:

Funding provided by: Japan Society for the Promotion of Science
ROR ID: https://ror.org/00hhkn466
Award Number:

Funding provided by: Uehara Memorial Foundation
ROR ID: https://ror.org/00gc20a07
Award Number:

Funding provided by: International Human Frontier Science Program Organization
ROR ID: https://ror.org/02ebx7v45
Award Number: LT0018/2022-L

Funding provided by: Daiichi Sankyo Foundation of Life Science
ROR ID: https://ror.org/05j492n53
Award Number:

Funding provided by: Nakatomi Foundation
ROR ID: https://ror.org/0196vdc40
Award Number:

Funding provided by: Burroughs Wellcome Fund
ROR ID: https://ror.org/01d35cw23
Award Number:

Funding provided by: National Cancer Institute
ROR ID: https://ror.org/040gcmg81
Award Number: K22CA237752

Funding provided by: National Cancer Institute
ROR ID: https://ror.org/040gcmg81
Award Number: R01CA258586

Funding provided by: National Cancer Institute
ROR ID: https://ror.org/040gcmg81
Award Number: U19CA264504

Funding provided by: Cancer Prevention and Research Institute of Texas
ROR ID: https://ror.org/0003xa228
Award Number: RR190034

Funding provided by: Sontag Foundation
ROR ID: https://ror.org/01pkpj777
Award Number:

Funding provided by: Cholangiocarcinoma Foundation
ROR ID: https://ror.org/04fp9z389
Award Number:

Funding provided by: National Cancer Institute
ROR ID: https://ror.org/040gcmg81
Award Number: 1K99CA245194-01

Funding provided by: Massachusetts General Hospital
ROR ID: https://ror.org/002pd6e78
Award Number:

Funding provided by: Cholangiocarcinoma Foundation
ROR ID: https://ror.org/04fp9z389
Award Number:

Funding provided by: The Mochida Memorial Foundation
Award Number:

Funding provided by: Massachusetts General Hospital
ROR ID: https://ror.org/002pd6e78
Award Number:

Funding provided by: Lubin Family Foundation*
Crossref Funder Registry ID:
Award Number:

Funding provided by: Cholangiocarcinoma Foundation
ROR ID: https://ror.org/04fp9z389
Award Number:

Funding provided by: Massachusetts General Hospital
ROR ID: https://ror.org/002pd6e78
Award Number:

Methods

Supplemental table for the analyses of transposable elements from mutant IDH1 cancer cell lines treated with mIDH1 inhibitor by two pipelines (TEtranscript and SQuIRE)

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