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

Michael D. Crowther, Garry Dolton, Mateusz Legut, Marine E. Caillaud, Angharad Lloyd, Meriem Attaf, Sarah A.E. 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

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14 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)178-185
Number of pages8
JournalNature Immunology
Volume21
Issue number2
DOIs
Publication statusPublished - Feb 2020

Keywords

  • biotechnology
  • cancer immunotherapy
  • immune cell isolation
  • t-cell receptor

Cite this

Crowther, M. D., Dolton, G., Legut, M., Caillaud, M. E., Lloyd, A., Attaf, M., Galloway, S. A. E., Rius, C., Farrell, C. P., Szomolay, B., Ager, A., Parker, A. L., Fuller, A., Donia, M., McCluskey, J., Rossjohn, J., Svane, I. M., Phillips, J. D., & Sewell, A. K. (2020). Genome-wide CRISPR–Cas9 screening reveals ubiquitous T cell cancer targeting via the monomorphic MHC class I-related protein MR1. Nature Immunology, 21(2), 178-185. https://doi.org/10.1038/s41590-019-0578-8