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. 2020 Feb;21(2):178-185.
doi: 10.1038/s41590-019-0578-8. Epub 2020 Jan 20.

Genome-wide CRISPR-Cas9 Screening Reveals Ubiquitous T Cell Cancer Targeting via the Monomorphic MHC Class I-related Protein MR1

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Free PMC article

Genome-wide CRISPR-Cas9 Screening Reveals Ubiquitous T Cell Cancer Targeting via the Monomorphic MHC Class I-related Protein MR1

Michael D Crowther et al. Nat Immunol. .
Free PMC article

Erratum in

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.

Conflict of interest statement

Competing Interests

Cardiff University has filed patents based on these findings.

Comment in

  • 'Bohemian Rhapsody' of MR1T cells.
    Mori L, De Libero G. Mori L, et al. Nat Immunol. 2020 Feb;21(2):108-110. doi: 10.1038/s41590-019-0588-6. Nat Immunol. 2020. PMID: 31959981 No abstract available.
  • MR1-restricted pan-cancer T cells.
    Bird L. Bird L. Nat Rev Immunol. 2020 Mar;20(3):141. doi: 10.1038/s41577-020-0284-7. Nat Rev Immunol. 2020. PMID: 32024985 No abstract available.

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