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

• Published in: Nature communications 2020-06, Vol.11 (1), p.2908-2908, Article 2908
• Main Authors: Wu, Daichao, Gallagher, D. Travis, Gowthaman, Ragul, Pierce, Brian G., Mariuzza, Roy A.
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; 631/250; 631/45/535/1266; 631/535; Antigens, Neoplasm - chemistry; Binding Sites; Biotinylation; Cancer; Cell recognition; Cell therapy; Codon; Crystal structure; Crystallography, X-Ray; Epitopes; Escherichia coli - metabolism; Histocompatibility antigen HLA; HLA-A2 Antigen - chemistry; Humanities and Social Sciences; Humans; Immunotherapy, Adoptive; Ligands; Lymphocytes; Lymphocytes T; Lymphocytes, Tumor-Infiltrating - immunology; multidisciplinary; Mutants; Mutation; Neoantigens; Neoplasms - metabolism; p53 Protein; Peptides - chemistry; Protein Binding; Protein Conformation; Protein Folding; Receptors; Receptors, Antigen, T-Cell - metabolism; Science; Science (multidisciplinary); Software; Surface Plasmon Resonance; T cell receptors; T-Lymphocytes - immunology; Tumor Suppressor Protein p53 - chemistry; Tumors
• ISSN: 2041-1723; 2041-1723
• 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. Developing broadly applicable neoantigen-directed adoptive cell therapies (ACTs) is challenging because each cancer patient has an unique neoantigen repertoire. Here, the authors present the crystal structures of tumor-specific T cell receptors (TCRs) that recognize a shared neoepitope arising from the R175H driver mutation in the p53 oncogene (p53R175H) alone and bound to p53R175H–HLA-A2, which are of interest for the structure-guided design of TCRs to improve T cell potency for ACT.