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

Authors

Zhihui Duan, Jianfeng Zhao, Junping Wu, Yue Zhang, Ping Yuan, Yayun Zeng, Huimin Jin, Roy A Mariuzza, Daichao Wu

Published in

Acta crystallographica. Section D, Structural biology. Sep 01, 2026. Epub Sep 01, 2026.

Abstract

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.

PMID:
42599692
Bibliographic data and abstract were imported from PubMed on 15 Aug 2026.

Read full publication at:
Please sign in to see all details.

Stats

1-terrible, 9-excellent. How would you rate this publication? Sign in in to submit your rating.

Post a comment

You need to be signed in to post comments. You can sign in here.

Comments

There are no comments yet.