Mutant IDH1 inhibition induces dsDNA sensing to activate tumor immunity

Meng Ju Wu; Hiroshi Kondo; Ashwin V. Kammula; Lei Shi; Yi Xiao; Sofiene Dhiab; Qin Xu; Chloe J. Slater; Omar I. Avila; Joshua Merritt; Hiroyuki Kato; Prabhat Kattel; Jonathan Sussman; Ilaria Gritti; Jason Eccleston; Yi Sun; Hyo Min Cho; Kira Olander; Takeshi Katsuda; Diana D. Shi; Milan R. Savani; Bailey C. Smith; James M. Cleary; Raul Mostoslavsky; Vindhya Vijay; Yosuke Kitagawa; Hiroaki Wakimoto; Russell W. Jenkins; Kathleen B. Yates; Jihye Paik; Ania Tassinari; Duygu Hatice Saatcioglu; Adriana E. Tron; Wilhelm Haas; Daniel Cahill; Samuel K. McBrayer; Robert T. Manguso; Nabeel Bardeesy

doi:10.1126/science.adl6173

Mutant IDH1 inhibition induces dsDNA sensing to activate tumor immunity

Meng Ju Wu, Hiroshi Kondo, Ashwin V. Kammula, Lei Shi, Yi Xiao, Sofiene Dhiab, Qin Xu, Chloe J. Slater, Omar I. Avila, Joshua Merritt, Hiroyuki Kato, Prabhat Kattel, Jonathan Sussman, Ilaria Gritti, Jason Eccleston, Yi Sun, Hyo Min Cho, Kira Olander, Takeshi Katsuda, Diana D. ShiMilan R. Savani, Bailey C. Smith, James M. Cleary, Raul Mostoslavsky, Vindhya Vijay, Yosuke Kitagawa, Hiroaki Wakimoto, Russell W. Jenkins, Kathleen B. Yates, Jihye Paik, Ania Tassinari, Duygu Hatice Saatcioglu, Adriana E. Tron, Wilhelm Haas, Daniel Cahill, Samuel K. McBrayer, Robert T. Manguso, Nabeel Bardeesy

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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.

Original language	English (US)
Pages (from-to)	eadl6173
Journal	Science (New York, N.Y.)
Volume	385
Issue number	6705
DOIs	https://doi.org/10.1126/science.adl6173
State	Published - Jul 12 2024

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Wu, M. J., Kondo, H., Kammula, A. V., Shi, L., Xiao, Y., Dhiab, S., Xu, Q., Slater, C. J., Avila, O. I., Merritt, J., Kato, H., Kattel, P., Sussman, J., Gritti, I., Eccleston, J., Sun, Y., Cho, H. M., Olander, K., Katsuda, T., ... Bardeesy, N. (2024). Mutant IDH1 inhibition induces dsDNA sensing to activate tumor immunity. Science (New York, N.Y.), 385(6705), eadl6173. https://doi.org/10.1126/science.adl6173

Wu, MJ, Kondo, H, Kammula, AV, Shi, L, Xiao, Y, Dhiab, S, Xu, Q, Slater, CJ, Avila, OI, Merritt, J, Kato, H, Kattel, P, Sussman, J, Gritti, I, Eccleston, J, Sun, Y, Cho, HM, Olander, K, Katsuda, T, Shi, DD, Savani, MR, Smith, BC, Cleary, JM, Mostoslavsky, R, Vijay, V, Kitagawa, Y, Wakimoto, H, Jenkins, RW, Yates, KB, Paik, J, Tassinari, A, Saatcioglu, DH, Tron, AE, Haas, W, Cahill, D, McBrayer, SK, Manguso, RT & Bardeesy, N 2024, 'Mutant IDH1 inhibition induces dsDNA sensing to activate tumor immunity', Science (New York, N.Y.), vol. 385, no. 6705, pp. eadl6173. https://doi.org/10.1126/science.adl6173

@article{6057b1ae7f8442da952cc1132ee3eb54,

title = "Mutant IDH1 inhibition induces dsDNA sensing to activate tumor immunity",

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.",

author = "Wu, {Meng Ju} and Hiroshi Kondo and Kammula, {Ashwin V.} and Lei Shi and Yi Xiao and Sofiene Dhiab and Qin Xu and Slater, {Chloe J.} and Avila, {Omar I.} and Joshua Merritt and Hiroyuki Kato and Prabhat Kattel and Jonathan Sussman and Ilaria Gritti and Jason Eccleston and Yi Sun and Cho, {Hyo Min} and Kira Olander and Takeshi Katsuda and Shi, {Diana D.} and Savani, {Milan R.} and Smith, {Bailey C.} and Cleary, {James M.} and Raul Mostoslavsky and Vindhya Vijay and Yosuke Kitagawa and Hiroaki Wakimoto and Jenkins, {Russell W.} and Yates, {Kathleen B.} and Jihye Paik and Ania Tassinari and Saatcioglu, {Duygu Hatice} and Tron, {Adriana E.} and Wilhelm Haas and Daniel Cahill and McBrayer, {Samuel K.} and Manguso, {Robert T.} and Nabeel Bardeesy",

year = "2024",

month = jul,

day = "12",

doi = "10.1126/science.adl6173",

language = "English (US)",

volume = "385",

pages = "eadl6173",

journal = "Science (New York, N.Y.)",

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T1 - Mutant IDH1 inhibition induces dsDNA sensing to activate tumor immunity

AU - Wu, Meng Ju

AU - Kondo, Hiroshi

AU - Kammula, Ashwin V.

AU - Shi, Lei

AU - Xiao, Yi

AU - Dhiab, Sofiene

AU - Xu, Qin

AU - Slater, Chloe J.

AU - Avila, Omar I.

AU - Merritt, Joshua

AU - Kato, Hiroyuki

AU - Kattel, Prabhat

AU - Sussman, Jonathan

AU - Gritti, Ilaria

AU - Eccleston, Jason

AU - Sun, Yi

AU - Cho, Hyo Min

AU - Olander, Kira

AU - Katsuda, Takeshi

AU - Shi, Diana D.

AU - Savani, Milan R.

AU - Smith, Bailey C.

AU - Cleary, James M.

AU - Mostoslavsky, Raul

AU - Vijay, Vindhya

AU - Kitagawa, Yosuke

AU - Wakimoto, Hiroaki

AU - Jenkins, Russell W.

AU - Yates, Kathleen B.

AU - Paik, Jihye

AU - Tassinari, Ania

AU - Saatcioglu, Duygu Hatice

AU - Tron, Adriana E.

AU - Haas, Wilhelm

AU - Cahill, Daniel

AU - McBrayer, Samuel K.

AU - Manguso, Robert T.

AU - Bardeesy, Nabeel

PY - 2024/7/12

Y1 - 2024/7/12

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85198605261&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85198605261&partnerID=8YFLogxK

U2 - 10.1126/science.adl6173

DO - 10.1126/science.adl6173

M3 - Article

C2 - 38991060

AN - SCOPUS:85198605261

SN - 0036-8075

VL - 385

SP - eadl6173

JO - Science (New York, N.Y.)

JF - Science (New York, N.Y.)

IS - 6705

ER -

Mutant IDH1 inhibition induces dsDNA sensing to activate tumor immunity

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