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 ORCID: https://orcid.org/0000-0002-5375-5533, Ager, Ann ORCID: https://orcid.org/0000-0002-5763-8908, Parker, Alan L. ORCID: https://orcid.org/0000-0002-9302-1761, Fuller, Anna, Donia, Marco, McCluskey, James, Rossjohn, Jamie ORCID: https://orcid.org/0000-0002-2020-7522, Svane, Inge Marie, Phillips, John D. and Sewell, Andrew K. ORCID: https://orcid.org/0000-0003-3194-3135 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:	06 Nov 2024 06:30
URI:	https://orca.cardiff.ac.uk/id/eprint/128952

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