Genome-wide CRISPR-Cas9 Screening Reveals Ubiquitous T cell Cancer Targeting via the monomorphic MHC class I related protein MR1

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 non-cancerous cells. Unlike mucosal-associated invariant T (MAIT) 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 patient T cells enabled killing of autologous and non-autologous melanoma. These findings offer opportunities for HLA-independent, pan-cancer, pan-population immunotherapies.