Genome-wide CRISPR-Cas9 screening reveals ubiquitous T cell cancer targeting via the monomorphic MHC class I-related protein MR1.
Michael D CrowtherGarry DoltonMateusz LegutMarine E CaillaudAngharad LloydMeriem AttafSarah A E GallowayCristina RiusColin P FarrellBarbara SzomolayAnn AgerAlan L ParkerAnna FullerMarco DoniaJames McCluskeyJamie RossjohnInge Marie SvaneJohn D PhillipsAndrew K SewellPublished in: Nature immunology (2020)
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.
Keyphrases
- papillary thyroid
- crispr cas
- genome wide
- squamous cell
- induced apoptosis
- endothelial cells
- regulatory t cells
- dna methylation
- genome editing
- magnetic resonance
- magnetic resonance imaging
- cell cycle arrest
- acute myeloid leukemia
- ejection fraction
- chronic kidney disease
- stem cells
- end stage renal disease
- type diabetes
- newly diagnosed
- cell death
- gene expression
- prognostic factors
- adipose tissue
- childhood cancer
- induced pluripotent stem cells
- platelet rich plasma
- pi k akt
- peripheral blood