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

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    Author
    Crowther, MD; Dotlon, G; Legut, M; Caillaud, ME; Lloyd, A; Attaf, M; Galloway, SAE; Rius, C; Farrell, CP; Szomolay, B; ...
    Date
    2020-01-20
    Source Title
    Nature Immunology
    Publisher
    NATURE PUBLISHING GROUP
    University of Melbourne Author/s
    Rossjohn, Jamie; McCluskey, James
    Affiliation
    Microbiology and Immunology
    Chancellery Research
    Metadata
    Show full item record
    Document Type
    Journal Article
    Citations
    Crowther, M. D., Dotlon, 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), pp.178-+. https://doi.org/10.1038/s41590-019-0578-8.
    Access Status
    Access this item via the Open Access location
    URI
    http://hdl.handle.net/11343/254013
    DOI
    10.1038/s41590-019-0578-8
    Open Access URL
    http://europepmc.org/articles/pmc6983325?pdf=render
    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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