A Cancer Immunotherapy Holy Grail?

T cell-based immunotherapies, exemplified by CAR-T, have attracted much attention as a way to target cancers. Unfortunately, CAR-T is clinically efficacious against only a limited number of malignancies, with its development against solid tumors still in its infancy. However, in a recent Nature Immunology study, Crowther et al. describe a potentially revolutionary advance in clinical immuno-oncology with the discovery of a T cell receptor (TCR) that is active against a spectrum of cancers in an HLA-independent manner (1). The authors isolated a T-cell clone (MC.7.G5) that killed various types of cancer cells regardless of HLA signature, while leaving noncancerous cells unharmed. After performing TCR sequencing, a genome-wide CRISPR-Cas9 screen revealed that killing was mediated through the monomorphic MHC class I-related protein MR1, which is broadly expressed and binds nonpeptide ligands that include metabolic intermediates. Intriguingly, TCR recognition of MR1 appeared to require bound ligand specific to cancer cells, suggesting that the T cell was detecting cancer cell metabolites presented by MR1. Additional studies demonstrated that even activated, stressed, or infected healthy cells were spared by MC.7.G5, and that in vivo killing of human Jurkat cells introduced into MC.7.G5-bearing NSG mice was evident. Excitingly, transduction of the MC.7.G5 TCR into T cells from advanced-stage melanoma patients led to lethality of both autologous and nonautologous melanomas. Thus, the authors have identified a TCR on their MC.7.G5 clone that may have opened the door to a cancer immunotherapy strategy with possibly universal clinical value.