Mutant IDH1 inhibition induces dsDNA sensing to activate tumor immunity

• Published in: Science (American Association for the Advancement of Science) Vol. 385; no. 6705; p. eadl6173
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States The American Association for the Advancement of Science 12.07.2024
• Subjects: Animal models; Animals; Antitumor activity; Antiviral drugs; Bioaccumulation; Brain; Brain cancer; Brain tumors; Cancer; CD8 antigen; Cell activation; Cell culture; Cell Line, Tumor; Cell proliferation; Cytosol; Cytotoxicity; Dehydrogenase; Dehydrogenases; Demethylation; Deoxyribonucleic acid; DNA; DNA - metabolism; DNA Demethylation; DNA Methylation; DNA Transposable Elements; Enzymes; Epigenesis, Genetic; Epigenetics; Gene silencing; Genes; Genomes; Glutarates - metabolism; Hepatocytes; Humans; Immune Evasion - genetics; Immune response; Immunity; Immunity, Innate - genetics; Immunosurveillance; Inactivation; Inhibition; Interferon; Isocitrate Dehydrogenase - genetics; Isocitrate Dehydrogenase - metabolism; Liver cancer; Logical Thinking; Lymphocytes; Lymphocytes T; Metabolic pathways; Metabolism; Metastases; Mice; Mimicry; Mutants; Mutation; Neoplasms - genetics; Neoplasms - immunology; Nucleic acids; Nucleotidyltransferases - genetics; Recruitment; Sensors; Signal transduction; Stimulation; Surveillance; Transposons; Tumor cells; Tumor Escape; Tumors
• ISSN: 0036-8075; 1095-9203; 1095-9203
• DOI: 10.1126/science.adl6173

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. Transposable elements (TEs) are relics of ancient viral infections scattered throughout mammalian genomes. TE reactivation and detection by cytosolic nucleic acid sensors acts as a cellular alarm, eliciting antiviral immunity (viral mimicry). Wu et al . report a new pathway for viral mimicry underlying the anticancer mechanism of mutant isocitrate dehydrogenase (mIDH1) inhibitors (see the Perspective by Pitarresi and Fitzgerald). mIDH1 affects cancer by producing the oncometabolite 2-hydroxyglutarate, which inactivates DNA- and histone-demethylating enzymes. The researchers show that the double-stranded DNA sensor cGAS is silenced by promoter DNA hypermethylation in mIDH1 liver and brain tumors. Conversely, mIDH1 inhibition causes DNA hypomethylation and transcriptional activation of cGAS, which results in the stimulation of a potent antitumor T cell response. —Pricilla N. Kelly