突变型IDH1抑制诱导dsDNA感应激活肿瘤免疫

SCI

11 August 2024

_{Mutant IDH1 inhibition induces dsDNA sensing to activate tumor immunity}

_{(Science；IF：44.7)}

• 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. Mutant IDH1 inhibition induces dsDNA sensing to activate tumor immunity. Science. 2024 Jul 12;385(6705):eadl6173. doi: 10.1126/science.adl6173. Epub 2024 Jul 12. PMID: 38991060.

• Corresponding authors：Robert T. Manguso, Krantz Family Center for Cancer Research, Massachusetts,General Hospital, Boston MA, USA.,Email: [e-mail]，Nabeel Bardeesy, Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston MA, USA.Email: [e-mail] (N.B.)
  

Abstract 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.

异柠檬酸脱氢酶1（IDH1）是在人类癌症中最常见的突变代谢基因。突变的IDH1（mIDH1）会产生致癌代谢物(R)-2-羟基戊二酸，这种代谢物会干扰与表观遗传学和其他过程相关的酶。IDH1突变型实体肿瘤的一个标志是T细胞排斥，而在临床前模型中抑制mIDH1可以恢复抗肿瘤免疫。在此，我们定义了一种由mIDH1驱动的免疫逃逸的细胞自主机制。IDH1突变型实体肿瘤表现出胞浆双链DNA（dsDNA）传感器cGAS的选择性高甲基化和转录沉默，从而损害了先天免疫信号传导。mIDH1抑制能够去除DNA的甲基化，解除对cGAS和转座子（TE）亚类的抑制。TE逆转录酶（TE-RT）产生的双链DNA激活cGAS，触发病毒模拟并刺激抗肿瘤免疫。总之，我们证明了mIDH1通过表观遗传途径抑制先天免疫，并将内源性逆转录酶活性与一种美国食品药品监督管理局批准的抗癌药物的作用机制联系了起来。