研究人员比较了副代谢物D-2-羟基戊二酸(D-2HG)和它的对映体L-2HG,发现肿瘤衍生的D-2HG被CD8+T细胞吸收,并以急性和可逆的方式改变了它们的代谢和抗肿瘤功能。研究人员确定糖酵解酶乳酸脱氢酶(LDH)是D-2HG的分子靶点。D-2HG和对LDH的抑制驱动了一种代谢程序和免疫CD8+T细胞特征,其特征是细胞毒性降低和干扰素-γ信号受损,这在人类异柠檬酸脱氢酶1(IDH1)突变胶质瘤患者的临床样本中得到了重现。
据介绍,人类癌症中的IDH功能突变导致D-2HG的产生,这是一种通过表观遗传学改变促进肿瘤发生的副代谢物。D-2HG的癌细胞内生作用已被充分了解,但其肿瘤细胞的非自主作用仍未得到充分的探讨。
附:英文原文
Title: Oncometabolite d-2HG alters T cell metabolism to impair CD8+ T cell function
Author: Giulia Notarangelo, Jessica B. Spinelli, Elizabeth M. Perez, Gregory J. Baker, Kiran Kurmi, Ilaria Elia, Sylwia A. Stopka, Gerard Baquer, Jia-Ren Lin, Alexandra J. Golby, Shakchhi Joshi, Heide F. Baron, Jefte M. Drijvers, Peter Georgiev, Alison E. Ringel, Elma Zaganjor, Samuel K. McBrayer, Peter K. Sorger, Arlene H. Sharpe, Kai W. Wucherpfennig, Sandro Santagata, Nathalie Y. R. Agar, Mario L. Suvà, Marcia C. Haigis
Issue&Volume: 2022-09-30
Abstract: Gain-of-function mutations in isocitrate dehydrogenase (IDH) in human cancers result in the production of D-2-hydroxyglutarate (D-2HG), an oncometabolite that promotes tumorigenesis through epigenetic alterations. The cancer cell–intrinsic effects of D-2HG are well understood, but its tumor cell–nonautonomous roles remain poorly explored. We compared the oncometabolite D-2HG with its enantiomer, L-2HG, and found that tumor-derived D-2HG was taken up by CD8+ T cells and altered their metabolism and antitumor functions in an acute and reversible fashion. We identified the glycolytic enzyme lactate dehydrogenase (LDH) as a molecular target of D-2HG. D-2HG and inhibition of LDH drive a metabolic program and immune CD8+ T cell signature marked by decreased cytotoxicity and impaired interferon-γ signaling that was recapitulated in clinical samples from human patients with IDH1 mutant gliomas.
DOI: abj5104
Source: https://www.science.org/doi/10.1126/science.abj5104