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

Nat Commun. 2020 Jun 9;11(1):2908. doi: 10.1038/s41467-020-16755-y.


Adoptive 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Antigens, Neoplasm / chemistry*
  • Binding Sites
  • Biotinylation
  • Codon
  • Crystallography, X-Ray
  • Epitopes
  • Escherichia coli / metabolism
  • HLA-A2 Antigen / chemistry*
  • Humans
  • Immunotherapy, Adoptive
  • Ligands
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Mutation*
  • Neoplasms / metabolism
  • Peptides / chemistry
  • Protein Binding
  • Protein Conformation
  • Protein Folding
  • Receptors, Antigen, T-Cell / metabolism
  • Software
  • Surface Plasmon Resonance
  • T-Lymphocytes / immunology*
  • Tumor Suppressor Protein p53 / chemistry*


  • Antigens, Neoplasm
  • Codon
  • Epitopes
  • HLA-A2 Antigen
  • Ligands
  • Peptides
  • Receptors, Antigen, T-Cell
  • TP53 protein, human
  • Tumor Suppressor Protein p53