Genome-wide CRISPR-Cas9 screening reveals ubiquitous T cell cancer targeting via the monomorphic MHC class I-related protein MR1
Genome-wide CRISPR-Cas9 screening reveals ubiquitous T cell cancer targeting via the monomorphic MHC class I-related protein MR1
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DOI：
10.1038/s41590-019-0578-8
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发表时间：
2020-01-20
影响因子：
30.5
通讯作者：
Sewell, Andrew K.
中科院分区：
文献类型：
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作者：
Crowther, Michael D.;Dotlon, Garry;Sewell, Andrew K.
人类白细胞抗原（HLA）-独立的，T细胞介导的靶向癌细胞将允许免疫破坏所有个体的恶性肿瘤。在这里，我们使用全基因组CRISPR-Cas9筛选来确定T细胞受体（TCR）通过单态MHC I类相关蛋白MR 1识别并杀死大多数人类癌症类型，同时对非癌细胞保持惰性。与粘膜相关的不变T细胞不同，TCR对靶细胞的识别不依赖于细菌负载。此外，MR 1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的TCR识别，表明识别通过感测癌症代谢物组而发生。MR 1限制性T细胞克隆介导白血病的体内消退并赋予NSG小鼠增强的存活。TCR转移到患者的T细胞能够杀死自体和非自体黑色素瘤。这些发现为HLA非依赖性、泛癌症、泛人群免疫治疗提供了机会。识别可作为T细胞靶点的选择性肿瘤相关分子是免疫治疗的主要目标。休厄尔及其同事证明，非经典MHC分子MR 1在多种癌症类型上表达，并且可以被常规T细胞靶向。
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.Identifying selective tumor-associated molecules that can act as targets for T cells is a major goal of immunotherapy. Sewell and colleagues demonstrate that the nonclassical MHC molecule MR1 is expressed on a wide variety of cancer types and can be targeted by conventional T cells.