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. [email protected].
  • 10. Systems Immunity Research Institute, Cardiff University, Cardiff, UK. [email protected].
  • # 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.