Structural basis for oligoclonal T cell recognition of a shared p53 cancer neoantigen

Published

June 9, 2020

Author(s)

David Travis Gallagher, Roy A. Mariuzza, Brian G. Pierce, Daichao Wu, Ragul Gowthaman

Abstract

AbstractAdoptive cell therapy (ACT) with tumor-specific T cells can mediate cancer regression. The main target of tumor-specific T cells are neoantigens arising from mutations in self-proteins. Although the majority of cancer neoantigens are unique to each patient, and therefore not broadly useful for ACT, some are shared. We studied oligoclonal T-cell receptors (TCRs) that recognize a shared neoepitope arising from a driver mutation in the p53 oncogene (p53R175H) presented by HLA-A2. Here we report structures of wild-type and mutant p53–HLA-A2 ligands, as well as structures of three tumor-specific TCRs bound to p53R175H–HLA-A2. These structures reveal how a driver mutation in p53 rendered a self-peptide visible to T cells. The TCRs employ structurally distinct strategies that are highly focused on the mutation to discriminate between mutant and wild-type p53. The TCR–p53R175H–HLA-A2 complexes provide a framework for designing TCRs to improve potency for ACT without sacrificing specificity.

Citation

Nature Communications

Volume

11

Issue

1

Pub Type

Journals

Download Paper

DOI Link

Keywords

binding, crystal structure, protein, T-Cell Receptor

Citation

Gallagher, D. , Mariuzza, R. , Pierce, B. , Wu, D. and Gowthaman, R. (2020), Structural basis for oligoclonal T cell recognition of a shared p53 cancer neoantigen, Nature Communications, [online], https://doi.org/10.1038/s41467-020-16755-y (Accessed July 13, 2025)