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

MD Crowther; G Dolton; M Legut; ME Caillaud; A Lloyd; M Attaf; SAE Galloway; C Rius; CP Farrell; B Szomolay; A Ager; AL Parker; A Fuller; M Donia; J McCluskey; J Rossjohn; IM Svane; JD Phillips; AK Sewell

Journal article

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

MD Crowther, G Dolton, M Legut, ME Caillaud, A Lloyd, M Attaf, SAE Galloway, C Rius, CP Farrell, B Szomolay, A Ager, AL Parker, A Fuller, M Donia, J McCluskey, J Rossjohn, IM Svane, JD Phillips, AK Sewell

Nature Immunology | NATURE PORTFOLIO | Published : 2020

DOI: 10.1038/s41590-019-0578-8

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 ca..

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University of Melbourne Researchers

James McCluskey Author

Jamie Rossjohn Author

Related Projects (1)

ANTIGEN PRESENTATION, RECOGNITION AND THE IMMUNE RESPONSE

This program focuses on understanding the development of immunity during infection or inflammatory diseases using a broad array of technique..

Grants

Awarded by Health and Care Research Wales

Funding Acknowledgements

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.