通過單態性MHC I類相關蛋白MR1可實現普遍性T細胞腫瘤靶向
作者：
小柯機器人發布時間：2020/1/25 10:53:32
英國卡迪夫大學Andrew K. Sewell課題組利用全基因組CRISPR–Cas9篩選揭示了通過單態性MHC I類相關蛋白MR1普遍性T細胞腫瘤靶向。這一研究成果於2020年1月20日在線發表在國際學術期刊《自然—免疫學》上。
研究人員使用全基因組CRISPR–Cas9篩選來確定了T細胞受體（TCR）通過單態MHC I類相關蛋白MR1識別並殺死了大多數人類癌症，同時對非癌細胞保持惰性。與黏膜相關恆定T細胞不同，TCR對靶細胞的識別獨立於細菌載量。此外，MR1的維生素B相關代謝物配體的濃度依賴性添加降低了癌細胞對TCR的識別，這表明識別是通過感測癌症代謝組而發生的。MR1限制性T細胞克隆介導了白血病的體內消退，並提高了NSG小鼠的存活率。將TCR轉移至患者的T細胞可殺死自體和非自體黑色素瘤。這些發現為不依賴人類白細胞抗原（HLA）的泛癌、泛人群免疫治療提供了機會。
據介紹，不依賴HLA、T細胞介導的癌細胞靶向能夠免疫清除所有個體的惡性腫瘤。
附：英文原文
Title: Genome-wide CRISPR–Cas9 screening reveals ubiquitous T cell cancer targeting via the monomorphic MHC class I-related protein MR1
Author: Michael D. Crowther, Garry Dolton, Mateusz Legut, Marine E. Caillaud, Angharad Lloyd, Meriem Attaf, Sarah A. E. Galloway, Cristina Rius, Colin P. Farrell, Barbara Szomolay, Ann Ager, Alan L. Parker, Anna Fuller, Marco Donia, James McCluskey, Jamie Rossjohn, Inge Marie Svane, John D. Phillips, Andrew K. Sewell
Issue&Volume: 2020-01-20
Abstract: Human leukocyte antigen (HLA)-independent, T cell–mediated targeting of cancer cells would allow immune destruction of malignancies in all individuals. Here, we use genome-wide CRISPR–Cas9 screening to establish that a T cell receptor (TCR) recognized and killed most human cancer types via the monomorphic MHC class I-related protein, MR1, while remaining inert to noncancerous cells. Unlike mucosal-associated invariant T cells, recognition of target cells by the TCR was independent of bacterial loading. Furthermore, concentration-dependent addition of vitamin B-related metabolite ligands of MR1 reduced TCR recognition of cancer cells, suggesting that recognition occurred via sensing of the cancer metabolome. An MR1-restricted T cell clone mediated in vivo regression of leukemia and conferred enhanced survival of NSG mice. TCR transfer to T cells of patients enabled killing of autologous and nonautologous melanoma. These findings offer opportunities for HLA-independent, pan-cancer, pan-population immunotherapies.
DOI: 10.1038/s41590-019-0578-8
Source: https://www.nature.com/articles/s41590-019-0578-8