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

Nat Immunol. 2020 Feb;21(2):178-185. doi: 10.1038/s41590-019-0578-8.

Michael D Crowther ^# ¹, Garry Dolton ^# ¹, Mateusz Legut ¹, Marine E Caillaud ¹, Angharad Lloyd ¹, Meriem Attaf ¹, Sarah A E Galloway ¹, Cristina Rius ¹, Colin P Farrell ², Barbara Szomolay ¹ ³, Ann Ager ¹ ³, Alan L Parker ⁴, Anna Fuller ¹, Marco Donia ⁵, James McCluskey ⁶, Jamie Rossjohn ¹ ³ ⁷ ⁸, Inge Marie Svane ⁵, John D Phillips ², Andrew K Sewell ⁹ ¹⁰

Affiliations

1 Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, UK.
2 Division of Hematology, University of Utah School of Medicine, Salt Lake City, UT, USA.
3 Systems Immunity Research Institute, Cardiff University, Cardiff, UK.
4 Division of Cancer and Genetics, Cardiff University School of Medicine, Cardiff, UK.
5 Center for Cancer Immune Therapy, Herlev Hospital, Copenhagen University, Copenhagen, Denmark.
6 Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria, Australia.
7 Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, Victoria, Australia.
8 Infection and Immunity Program & Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia.
9 Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, UK. sewellak@cardiff.ac.uk.
10 Systems Immunity Research Institute, Cardiff University, Cardiff, UK. sewellak@cardiff.ac.uk.
# Contributed equally.

PMID: 31959982 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 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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