Mutant IDH1 inhibition induces dsDNA sensing to activate tumor immunity

被引：11

作者：

Wu, Meng-Ju ^{[1
,2
,3
,4
]}

Kondo, Hiroshi ^{[1
,2
,3
,4
]}

Kammula, Ashwin V. ^{[1
,3
,4
]}

Shi, Lei ^{[1
,2
,3
,4
]}

Xiao, Yi ^{[5
]}

Dhiab, Sofiene ^{[1
,2
,3
,4
]}

Xu, Qin ^{[1
,2
,3
,4
]}

Slater, Chloe J. ^{[1
,2
,3
,6
,7
]}

Avila, Omar I. ^{[1
,3
,4
]}

Merritt, Joshua ^{[1
,2
,3
,4
]}

Kato, Hiroyuki ^{[1
,2
,3
,4
]}

Kattel, Prabhat ^{[1
,2
,3
,4
]}

Sussman, Jonathan ^{[8
,9
,10
]}

Gritti, Ilaria ^{[1
,2
,3
,4
]}

Eccleston, Jason ^{[8
,9
]}

Sun, Yi ^{[1
]}

Cho, Hyo Min ^{[1
,2
,3
,4
]}

Olander, Kira ^{[4
]}

Katsuda, Takeshi ^{[8
,9
]}

Shi, Diana D. ^{[5
,11
]}

Savani, Milan R. ^{[5
,12
]}

Smith, Bailey C. ^{[5
]}

Cleary, James M. ^{[13
]}

Mostoslavsky, Raul ^{[1
,2
,3
,4
]}

Vijay, Vindhya ^{[1
,2
,3
,4
]}

Kitagawa, Yosuke ^{[14
]}

Wakimoto, Hiroaki ^{[14
]}

Jenkins, Russell W. ^{[1
,3
,4
,15
]}

Yates, Kathleen B. ^{[1
,3
,4
]}

Paik, Jihye ^{[16
]}

Tassinari, Ania ^{[7
]}

Saatcioglu, Duygu Hatice ^{[7
]}

Tron, Adriana E. ^{[7
]}

Haas, Wilhelm ^{[1
,3
,4
]}

Cahill, Daniel ^{[14
]}

Mcbrayer, Samuel K. ^{[5
,17
]}

Manguso, Robert T. ^{[1
,3
,4
]}

Bardeesy, Nabeel ^{[1
,2
,3
,4
]}

机构：

[1] Massachusetts Gen Hosp, Krantz Family Ctr Canc Res, Boston, MA 02114 USA

[2] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA

[3] Harvard Med Sch, Dept Med, Boston, MA 02115 USA

[4] Massachusetts Inst Technol & Harvard, Broad Inst, Cambridge, MA 02139 USA

[5] Univ Texas Southwestern Med Ctr Dallas, Childrens Med Ctr Res Inst, Dallas, TX USA

[6] Univ Paris Saclay, Inst Gustave Roussy, INSERM, U1015, Villejuif, France

[7] Servier Pharmaceut LLC, Boston, MA USA

[8] Univ Penn, Perelman Sch Med, Abramson Family Canc Res Inst, Philadelphia, PA USA

[9] Univ Penn, Perelman Sch Med, Dept Med, Philadelphia, PA USA

[10] Univ Penn, Perelman Sch Med, Grad Grp Genom & Computat Biol, Philadelphia, PA USA

[11] Harvard Med Sch, Dept Radiat Oncol, Dana Farber Brigham & Womens Canc Ctr, Boston, MA 02115 USA

[12] Univ Texas Southwestern Med Ctr, Med Scientist Training Program, Dallas, TX USA

[13] Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, Div Gastrointestinal Oncol, Boston, MA USA

[14] Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA USA

[15] Harvard Med Sch, Harvard Program Therapeut Sci, Lab Syst Pharmacol, Boston, MA USA

[16] Cornell Univ, Weill Med Coll, Sandra & Edward Meyer Canc Ctr, Dept Pathol & Lab Med, New York, NY USA

[17] Univ Texas SouthWestern Med Ctr Dallas, Dept Pediat, Dallas, TX USA

来源：

SCIENCE | 2024年 / 385卷 / 6705期

基金：

美国国家卫生研究院; 日本学术振兴会;

关键词：

DIFFERENTIAL EXPRESSION ANALYSIS; REVERSE-TRANSCRIPTASE; ENDOGENOUS RETROVIRUSES; TRANSPOSABLE ELEMENTS; CELL-LINE; MUTATIONS; CANCER; (R)-2-HYDROXYGLUTARATE; IDENTIFICATION; MAINTENANCE;

D O I：

10.1126/science.adl6173

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：20

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