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通过单态性MHC I类相关蛋白MR1可实现普遍性T细胞肿瘤靶向
2020-01-25 10:53

英国卡迪夫大学Andrew K. Sewell课题组利用全基因组CRISPR–Cas9筛选揭示了通过单态性MHC I类相关蛋白MR1普遍性T细胞肿瘤靶向。这一研究成果于2020年1月20日在线发表在国际学术期刊《自然—免疫学》上。

研究人员使用全基因组CRISPR–Cas9筛选来确定了T细胞受体(TCR)通过单态MHC I类相关蛋白MR1识别并杀死了大多数人类癌症,同时对非癌细胞保持惰性。与粘膜相关恒定T细胞不同,TCR对靶细胞的识别独立于细菌载量。此外,MR1的维生素B相关代谢物配体的浓度依赖性添加降低了癌细胞对TCR的识别,这表明识别是通过感测癌症代谢组而发生的。MR1限制性T细胞克隆介导了白血病的体内消退,并提高了NSG小鼠的存活率。将TCR转移至患者的T细胞可杀死自体和非自体黑色素瘤。这些发现为不依赖人类白细胞抗原(HLA)的泛癌、泛人群免疫治疗提供了机会。
 
据介绍,不依赖HLA、T细胞介导的癌细胞靶向能够免疫清除所有个体的恶性肿瘤。
 
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

Nature Immunology:《自然—免疫学》,创刊于2000年。隶属于施普林格·自然出版集团,最新IF:31.25
官方网址:https://www.nature.com/ni/
投稿链接:https://mts-ni.nature.com/cgi-bin/main.plex


本期文章:《自然—免疫学》:Online/在线发表

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