Every year there are about four million new cases of cancer diagnosed in the world, with over eight million cancer-related deaths. There are over 100 different types of cancer, with often significant genotypic and phenotypic heterogeneity even among tumors of the same kind. Research is one of the best weapons to oppose this scourge, and great progress has been made in cancer diagnosis, treatment, and prevention. In addition, scientists have made enormous strides dissecting the mechanisms and pathways that drive carcinogenesis and metastasis, and in offering approaches as to how these processes can be potentially targeted for therapeutic purposes.
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.
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Reference:
1. Crowther et al. (2020) Nat Immunol. 2020 Feb;21(2):178-185.