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氧化脂质的摄取促进肿瘤中CD8+T细胞的脂质过氧化和功能障碍
作者:小柯机器人 发布时间:2021/6/9 14:32:52

美国索尔克生物研究所Susan M. Kaech、德国癌症研究中Guoliang Cui等研究人员合作发现,氧化脂质的摄取促进肿瘤中CD8+T细胞的脂质过氧化和功能障碍。相关论文于2021年6月7日在线发表在《免疫》杂志上。

研究人员揭示了CD8+肿瘤浸润淋巴细胞(TIL)如何对肿瘤微环境(TME)内的脂质作出反应。研究人员发现TME中几类脂质的浓度升高,并且这些脂质在CD8+TIL中积累。脂质积累与CD36(氧化脂质的清道夫受体)在CD8+TIL上的表达增加有关,这也与进行性T细胞功能障碍有关。与WT相比,Cd36-/-T 细胞在TME中保留了效应子功能。

从机制上讲,CD36促进氧化低密度脂蛋白(OxLDL)吸收到T细胞中,这会诱导脂质过氧化和p38激酶的下游激活。p38的抑制在体外恢复了效应T细胞的功能,并且通过谷胱甘肽过氧化物酶4的过表达来解决脂质过氧化,从而在体内恢复CD8+TIL的功能。因此,氧化脂质-CD36信号轴促进肿瘤内CD8+T细胞功能障碍,并可作为免疫疗法的治疗途径。

据了解,肿瘤微环境TME中常见的代谢改变是脂质积累,这是与免疫功能障碍相关的特征。

附:英文原文

Title: Uptake of oxidized lipids by the scavenger receptor CD36 promotes lipid peroxidation and dysfunction in CD8+ T cells in tumors

Author: Shihao Xu, Omkar Chaudhary, Patricia Rodríguez-Morales, Xiaoli Sun, Dan Chen, Roberta Zappasodi, Ziyan Xu, Antonio F.M. Pinto, April Williams, Isabell Schulze, Yagmur Farsakoglu, Siva Karthik Varanasi, Jun Siong Low, Wenxi Tang, Haiping Wang, Bryan McDonald, Victoria Tripple, Michael Downes, Ronald M. Evans, Nada A. Abumrad, Taha Merghoub, Jedd D. Wolchok, Maxim N. Shokhirev, Ping-Chih Ho, Joseph L. Witztum, Brinda Emu, Guoliang Cui, Susan M. Kaech

Issue&Volume: 2021-06-07

Abstract: A common metabolic alteration in the tumor microenvironment (TME) is lipid accumulation,a feature associated with immune dysfunction. Here, we examined how CD8+ tumor infiltrating lymphocytes (TILs) respond to lipids within the TME. We foundelevated concentrations of several classes of lipids in the TME and accumulation ofthese in CD8+ TILs. Lipid accumulation was associated with increased expression of CD36, a scavengerreceptor for oxidized lipids, on CD8+ TILs, which also correlated with progressive T cell dysfunction. Cd36/ T cells retained effector functions in the TME, as compared to WT counterparts. Mechanistically,CD36 promoted uptake of oxidized low-density lipoproteins (OxLDL) into T cells, andthis induced lipid peroxidation and downstream activation of p38 kinase. Inhibitionof p38 restored effector T cell functions in vitro, and resolution of lipid peroxidation by overexpression of glutathione peroxidase4 restored functionalities in CD8+ TILs in vivo. Thus, an oxidized lipid-CD36 axis promotes intratumoral CD8+ T cell dysfunction and serves as a therapeutic avenue for immunotherapies.

DOI: 10.1016/j.immuni.2021.05.003

Source: https://www.cell.com/immunity/fulltext/S1074-7613(21)00209-0

期刊信息

Immunity:《免疫》,创刊于1994年。隶属于细胞出版社,最新IF:21.522
官方网址:https://www.cell.com/immunity/home
投稿链接:https://www.editorialmanager.com/immunity/default.aspx