Genome-wide CRISPR-Cas9 screening reveals ubiquitous T cell cancer targeting via the monomorphic MHC class I-related protein MR1
Author
Crowther, MD; Dotlon, G; Legut, M; Caillaud, ME; Lloyd, A; Attaf, M; Galloway, SAE; Rius, C; Farrell, CP; Szomolay, B; ...Date
2020-01-20Source Title
Nature ImmunologyPublisher
NATURE PUBLISHING GROUPAffiliation
Microbiology and ImmunologyChancellery Research
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Crowther, M. D., Dotlon, G., Legut, M., Caillaud, M. E., Lloyd, A., Attaf, M., Galloway, S. A. E., Rius, C., Farrell, C. P., Szomolay, B., Ager, A., Parker, A. L., Fuller, A., Donia, M., McCluskey, J., Rossjohn, J., Svane, I. M., Phillips, J. D. & Sewell, A. K. (2020). Genome-wide CRISPR-Cas9 screening reveals ubiquitous T cell cancer targeting via the monomorphic MHC class I-related protein MR1. NATURE IMMUNOLOGY, 21 (2), pp.178-+. https://doi.org/10.1038/s41590-019-0578-8.Access Status
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http://europepmc.org/articles/pmc6983325?pdf=renderAbstract
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.
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