Flores-Villanueva Pedro, Sobhani Navid, Wang Xu, Li Yong
Department of Medicine, Section of Epidemiology and Population Sciences, Baylor College of Medicine, Houston, TX 77030, USA.
Cancers (Basel). 2020 Aug 3;12(8):2145. doi: 10.3390/cancers12082145.
Major histocompatibility complex class I-related (MR1) was first identified as a cell membrane protein involved in the development and expansion of a unique set of T cells expressing an invariant T-cell receptor (TCR) α-chain. These cells were initially discovered in mucosal tissues, such as the intestinal mucosa, so they are called mucosal-associated invariant T (MAIT) cells. MR1 senses the presence of intermediate metabolites of riboflavin and folic acid synthesis that have been chemically modified by the side-products of glycolysis, glyoxal or methylglyoxal. These modified metabolites form complexes with MR1 and translocate from the endoplasmic reticulum to the plasma membrane where MAIT cells' TCRs recognize them. Recent publications report that atypical MR1-restricted cytotoxic T cells, differing from MAIT cells in TCR usage, antigen, and transcription factor profile, recognize an as yet unknown cancer-specific metabolite presented by MR1 in cancer cells. This metabolite may represent another class of neoantigens, beyond the neo-peptides arising from altered tumor proteins. In an MR1-dependent manner, these MR1-restricted T cells, while sparing noncancerous cells, kill many cancer cell lines and attenuate cell-line-derived and patient-derived xenograft tumors. As MR1 is monomorphic and expressed in a wide range of cancer tissues, these findings raise the possibility of universal pan-cancer immunotherapies that are dependent on cancer metabolites.
主要组织相容性复合体I类相关分子（MR1）最初被鉴定为一种细胞膜蛋白，参与一组独特的表达恒定T细胞受体（TCR）α链的T细胞的发育和扩增。这些细胞最初在黏膜组织如肠黏膜中被发现，因此被称为黏膜相关恒定T（MAIT）细胞。MR1能感知核黄素和叶酸合成的中间代谢产物的存在，这些代谢产物已被糖酵解的副产物乙二醛或甲基乙二醛化学修饰。这些修饰后的代谢产物与MR1形成复合物，并从内质网转运至质膜，MAIT细胞的TCR在质膜上识别它们。最近的出版物报道，非典型的MR1限制性细胞毒性T细胞在TCR使用、抗原和转录因子谱方面与MAIT细胞不同，它们识别癌细胞中由MR1呈递的一种未知的癌症特异性代谢产物。这种代谢产物可能代表另一类新抗原，不同于由肿瘤蛋白改变产生的新肽。以MR1依赖的方式，这些MR1限制性T细胞在不损伤非癌细胞的情况下，杀死许多癌细胞系，并使源自细胞系和患者的异种移植肿瘤缩小。由于MR1是单态的且在多种癌症组织中表达，这些发现增加了依赖癌症代谢产物的通用泛癌免疫疗法的可能性。
