据介绍，异柠檬酸脱氢酶1（IDH1）是人类癌症中最常见的突变代谢基因。突变IDH1（mIDH1）产生肿瘤代谢产物（R）-2-羟基戊二酸，破坏参与表观遗传学和其他过程的酶。IDH1突变实体瘤的一个标志是T细胞排斥，而临床前模型中mIDH1的抑制可以恢复抗肿瘤免疫。
研究人员定义了mIDH1驱动的免疫逃避的细胞自主机制。IDH1突变实体瘤表现出细胞质双链DNA（dsDNA）传感器CGAS的选择性高甲基化和沉默，损害了先天免疫信号传导。mIDH1抑制可恢复DNA去甲基化、去抑制CGAS和转座因子（TE）亚类。TE逆转录酶（TE-RT）产生的dsDNA激活cGAS，引发病毒模拟，刺激抗肿瘤免疫。
总之，这一研究证明mIDH1表观遗传学抑制先天免疫，并将内源性RT活性与美国食品和药物管理局（FDA）批准的肿瘤药物作用机制联系起来。
附：英文原文
Title: Mutant IDH1 inhibition induces dsDNA sensing to activate tumor immunity
Author: 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
Issue&Volume: 2024-07-12
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.
DOI: adl6173
Source: https://www.science.org/doi/10.1126/science.adl6173