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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The datasets generated during the current study are available from the corresponding author upon reasonable request.
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We thank F. Zhang for deposition of the GeCKO v.2 library at the Addgene plasmid repository (Addgene plasmid no. 1000000048); D. Trono for the deposition of pRRL.sin.cppt.pgk-gfp.wpre (Addgene plasmid no. 12252), envelope plasmid pMD2.G (Addgene plasmid no. 12259), and packaging plasmids pMDLg/pRRE (Addgene plasmid no. 12251) and pRSV-Rev (Addgene plasmid no. 12253); and J. Riley, University of Pennsylvania, who kindly provided the pELNS vector. A.K.S. is a Welcome Senior Investigator (WT100327MA), M.D.C. was funded by the Welsh Assembly Government via a Health and Care Research Wales PhD studentship. M.L. is funded by a Consolidator Award via the Wellcome Institutional Strategic Support Fund to the Cardiff University College of Biomedical and Life Sciences. S.A.E.G. was funded by a Tenovus Cancer Care PhD studentship. J.M. was supported by Program Grant APP1113293 from the National Health and Medical Research Council Australia.
Cardiff University has filed patents based on these findings.
Peer review information Zoltan Fehervari was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.
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Crowther, M.D., Dolton, G., Legut, M. et al. Genome-wide CRISPR–Cas9 screening reveals ubiquitous T cell cancer targeting via the monomorphic MHC class I-related protein MR1. Nat Immunol 21, 178–185 (2020). https://doi.org/10.1038/s41590-019-0578-8