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

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TitleStructural basis for oligoclonal T cell recognition of a shared p53 cancer neoantigen.
Publication TypeJournal Article
Year of Publication2020
AuthorsWu, D, D Gallagher, T, Gowthaman, R, Pierce, BG, Mariuzza, RA
JournalNat Commun
Volume11
Issue1
Pagination2908
Date Published2020 Jun 09
ISSN2041-1723
Abstract

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.

DOI10.1038/s41467-020-16755-y
Alternate JournalNat Commun
PubMed ID32518267
PubMed Central IDPMC7283474
Grant ListGM126299 / / U.S. Department of Health & Human Services | National Institutes of Health (NIH) /
AI129893 / / U.S. Department of Health & Human Services | National Institutes of Health (NIH) /