%0 Journal Article %1 Crowther:2020:Nat-Immunol:31959982 %A Crowther, M D %A Dolton, G %A Legut, M %A Caillaud, M E %A Lloyd, A %A Attaf, M %A Galloway, S A E %A Rius, C %A Farrell, C P %A Szomolay, B %A Ager, A %A Parker, A L %A Fuller, A %A Donia, M %A McCluskey, J %A Rossjohn, J %A Svane, I M %A Phillips, J D %A Sewell, A K %D 2020 %J Nat Immunol %K cancer-research immunotherapy mustread paywall t-cell %R 10.1038/s41590-019-0578-8 %T Genome-wide CRISPR-Cas9 screening reveals ubiquitous T cell cancer targeting via the monomorphic MHC class I-related protein MR1 %U https://www.ncbi.nlm.nih.gov/pubmed/?term=10.1038%2Fs41590-019-0578-8 %X 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.

@article{Crowther:2020:Nat-Immunol:31959982, 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.}, added-at = {2020-01-22T20:16:02.000+0100}, author = {Crowther, M D and Dolton, G and Legut, M and Caillaud, M E and Lloyd, A and Attaf, M and Galloway, S A E and Rius, C and Farrell, C P and Szomolay, B and Ager, A and Parker, A L and Fuller, A and Donia, M and McCluskey, J and Rossjohn, J and Svane, I M and Phillips, J D and Sewell, A K}, biburl = {https://www.bibsonomy.org/bibtex/23053a47390fca0d367f8fd6377368c83/marcsaric}, description = {Genome-wide CRISPR-Cas9 screening reveals ubiquitous T cell cancer targeting via the monomorphic MHC class I-related protein MR1. - PubMed - NCBI}, doi = {10.1038/s41590-019-0578-8}, interhash = {5b63c8a8e02b6dbc401df06a31e8eafd}, intrahash = {3053a47390fca0d367f8fd6377368c83}, journal = {Nat Immunol}, keywords = {cancer-research immunotherapy mustread paywall t-cell}, month = jan, pmid = {31959982}, timestamp = {2020-01-22T20:16:02.000+0100}, title = {Genome-wide CRISPR-Cas9 screening reveals ubiquitous T cell cancer targeting via the monomorphic MHC class I-related protein MR1}, url = {https://www.ncbi.nlm.nih.gov/pubmed/?term=10.1038%2Fs41590-019-0578-8}, year = 2020 }