Genome-wide CRISPR-Cas9 screening reveals ubiquitous T cell cancer targeting via the monomorphic MHC class I-related protein MR1

Crowther, Michael D., Dolton, Garry, Legut, Mateusz, Caillaud, Marine E., Lloyd, Angharad, Attaf, Meriem, Galloway, Sarah A. E., Rius, Cristina, Farrell, Colin P., Szomolay, Barbara, Ager, Ann, Parker, Alan L., Fuller, Anna, Donia, Marco, McCluskey, James, Rossjohn, Jamie, Svane, Inge Marie, Phillips, John D. and Sewell, Andrew 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 , 178 - 185. 10.1038/s41590-019-0578-8

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Abstract

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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Publisher:	Nature Publishing Group
ISSN:	1529-2908
Date of First Compliant Deposit:	28 January 2020
Date of Acceptance:	10 December 2019
Last Modified:	20 Jan 2021 04:16
URI:	http://orca.cf.ac.uk/id/eprint/128952

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