Structural basis for T-cell receptor recognition of p53 ^Y220D , a human cancer neoantigen

Adoptive cell therapy (ACT) with tumor-specific T cells can mediate durable cancer regression. The main target of tumor-specific T cells are neoantigens resulting from mutations in self-antigens over the course of malignant transformation. To understand T-cell recognition of cancer neoantigens at the atomic level, we studied a T-cell receptor (TCR 4414A) that recognizes a neoepitope arising from a driver mutation in the p53 oncogene (p53 Y220D ) presented by HLA-A2. Here, we report the structure of TCR 4414A bound to HLA-A2 and p53 Y220D , as well as structures of unbound wild-type and mutant p53–HLA-A2 ligands. The structures reveal that the Y220D mutation induces a conformational change in the p53 Y220D neoepitope that is detected by TCR 4414A, thereby rendering a normally cryptic self-peptide visible to T cells. The TCR minimizes interactions with the N- and C-terminal portions of p53 Y220D , which are identical in mutant and wild-type peptides, and instead focuses on the Y220D driver mutation at the peptide center. In this way, TCR 4414A achieves highly specific recognition of mutant over wild-type p53, a critical parameter for avoiding off-target toxicities in ACT.