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

Daichao Wu, D. Travis Gallagher, Ragul Gowthaman, Brian G. Pierce and Roy A. Mariuzza ()
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Daichao Wu: University of Maryland Institute for Bioscience and Biotechnology Research
D. Travis Gallagher: University of Maryland Institute for Bioscience and Biotechnology Research
Ragul Gowthaman: University of Maryland Institute for Bioscience and Biotechnology Research
Brian G. Pierce: University of Maryland Institute for Bioscience and Biotechnology Research
Roy A. Mariuzza: University of Maryland Institute for Bioscience and Biotechnology Research

Nature Communications, 2020, vol. 11, issue 1, 1-12

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-16755-y

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