21gj
Neoantigen p53Y220D-HLA-A2
Structural highlights
FunctionPublication Abstract from PubMedAdoptive 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. Structural basis for T-cell receptor recognition of p53(Y220D), a human cancer neoantigen.,Duan Z, Zhao J, Wu J, Zhang Y, Yuan P, Zeng Y, Jin H, Mariuzza RA, Wu D Acta Crystallogr D Struct Biol. 2026 Sep 1;82(Pt 9):1082-1092. doi: , 10.1107/S2059798326007564. Epub 2026 Aug 14. PMID:42599692[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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