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Summary  Antigen‐specific  T  cell receptor ( TCR ) gene transfer via patient‐derived  T  cells is an attractive approach to cancer therapy, with the potential to circumvent immune regulatory networks. However, high‐affinity tumour‐specific  TCR  clonotypes are typically deleted from the available repertoire during thymic selection because the vast majority of targeted epitopes are derived from autologous proteins. This process places intrinsic constraints on the efficacy of  T  cell‐based cancer vaccines and therapeutic strategies that employ naturally generated tumour‐specific  TCRs . In this study, we used altered peptide ligands and lentivirus‐mediated transduction of affinity‐enhanced  TCRs  selected by phage display to study the functional properties of  CD8 +  T  cells specific for three different tumour‐associated peptide antigens across a range of binding parameters. The key findings were: (i)  TCR  affinity controls  T  cell antigen sensitivity and polyfunctionality; (ii) supraphysiological affinity thresholds exist, above which  T  cell function cannot be improved; and (iii)  T  cells transduced with very high‐affinity  TCRs  exhibit cross‐reactivity with self‐derived peptides presented by the restricting human leucocyte antigen. Optimal system‐defined affinity windows above the range established for natural tumour‐specific  TCRs  therefore allow the enhancement of  T  cell effector function without off‐target effects. These findings have major implications for the rational design of novel  TCR ‐based biologics underpinned by rigorous preclinical evaluation.

T cell receptor binding affinity governs the functional profile of cancer‐specific CD8 + T cells