Genome-wide CRISPR-Cas9 screening reveals ubiquitous T cell cancer targeting via the monomorphic MHC class I-related protein MR1
AuthorCrowther, MD; Dotlon, G; Legut, M; Caillaud, ME; Lloyd, A; Attaf, M; Galloway, SAE; Rius, C; Farrell, CP; Szomolay, B; ...
Source TitleNature Immunology
PublisherNATURE PUBLISHING GROUP
AffiliationMicrobiology and Immunology
Document TypeJournal Article
CitationsCrowther, 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 StatusAccess this item via the Open Access location
Open Access URLAccepted version
NHMRC Grant codeNHMRC/1113293
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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