Identification of human T-cell receptors with optimal affinity to cancer antigens using antigen-negative humanized mice

T cell receptor (TCR) or chimeric antigen receptor gene therapy, the grafting of antigen specificity onto patients’ T cells followed by their use for cancer therapy, can be very effective1. Problems are to choose a suitable target antigen2 and to obtain optimal-affinity TCRs against tumor-associated antigens, as these self-proteins likely cause deletional tolerance of high-avidity T cells3. The cancer/testis (CT) antigen MAGE-A1 could be an attractive target because of its limited expression in normal cells and reactivation in cancer cells4. It is unknown whether CT antigens induce tolerance. Here, we describe the generation and characterization of MAGE-A1-specific TCRs from antigen-negative mice with a diverse human TCR repertoire restricted to HLA-A25. By comparison, human-derived TCRs are likely skewed towards low-affinity, compatible with tolerance. The humanized mice provide a powerful tool to generate optimal-affinity TCRs, which are difficult, if at all, accessible in humans.