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

Michael D Crowther; Garry Dotlon; Mateusz Legut; Marine E Caillaud; Angharad Lloyd; Meriem Attaf; Sarah AE Galloway; Cristina Rius; Colin P Farrell; Barbara Szomolay; Ann Ager; Alan L Parker; Anna Fuller; Marco Donia; James McCluskey; Jamie Rossjohn; Inge Marie Svane; John D Phillips; Andrew K Sewell

Journal article

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

Michael D Crowther, Garry Dotlon, Mateusz Legut, Marine E Caillaud, Angharad Lloyd, Meriem Attaf, Sarah AE Galloway, Cristina Rius, Colin P Farrell, Barbara Szomolay, Ann Ager, Alan L Parker, Anna Fuller, Marco Donia, James McCluskey, Jamie Rossjohn, Inge Marie Svane, John D Phillips, Andrew K Sewell

Nature Immunology | NATURE PUBLISHING GROUP | 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 Microbiology and Immunology

Grants

Awarded by Welsh Assembly Government via a Health and Care Research Wales PhD studentship

Awarded by National Health and Medical Research Council Australia

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.