期刊
NATURE IMMUNOLOGY
卷 21, 期 2, 页码 178-+出版社
NATURE PORTFOLIO
DOI: 10.1038/s41590-019-0578-8
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资金
- Welsh Assembly Government via a Health and Care Research Wales PhD studentship [WT100327MA]
- Wellcome Institutional Strategic Support Fund
- Tenovus Cancer Care PhD studentship
- National Health and Medical Research Council Australia [APP1113293]
- BBSRC [BB/S002480/1] Funding Source: UKRI
- MRC [MR/L008742/1] Funding Source: UKRI
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.
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