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

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.

Authors:
 [1];  [2]; ORCiD logo [3]; ORCiD logo [3];  [3]
  1. Univ. of Maryland, Rockville, MD (United States); Univ. of Maryland, College Park, MD (United States); Univ. of South China, Hunan (China)
  2. Univ. of Maryland, Rockville, MD (United States); National Inst. of Standards and Technology (NIST), Boulder, CO (United States)
  3. Univ. of Maryland, Rockville, MD (United States); Univ. of Maryland, College Park, MD (United States)
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
National Institutes of Health (NIH); USDOE
OSTI Identifier:
1633804
Resource Type:
Accepted Manuscript
Journal Name:
Nature Communications
Additional Journal Information:
Journal Volume: 11; Journal Issue: 1; Journal ID: ISSN 2041-1723
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
ENGLISH
Subject:
60 APPLIED LIFE SCIENCES

Citation Formats

Wu, Daichao, Gallagher, D. Travis, Gowthaman, Ragul, Pierce, Brian G., and Mariuzza, Roy A.. Structural basis for oligoclonal T cell recognition of a shared p53 cancer neoantigen. United States: N. p., 2020. Web. https://doi.org/10.1038/s41467-020-16755-y.
Wu, Daichao, Gallagher, D. Travis, Gowthaman, Ragul, Pierce, Brian G., & Mariuzza, Roy A.. Structural basis for oligoclonal T cell recognition of a shared p53 cancer neoantigen. United States. https://doi.org/10.1038/s41467-020-16755-y
Wu, Daichao, Gallagher, D. Travis, Gowthaman, Ragul, Pierce, Brian G., and Mariuzza, Roy A.. Tue . "Structural basis for oligoclonal T cell recognition of a shared p53 cancer neoantigen". United States. https://doi.org/10.1038/s41467-020-16755-y. https://www.osti.gov/servlets/purl/1633804.
@article{osti_1633804,
title = {Structural basis for oligoclonal T cell recognition of a shared p53 cancer neoantigen},
author = {Wu, Daichao and Gallagher, D. Travis and Gowthaman, Ragul and Pierce, Brian G. and Mariuzza, Roy A.},
abstractNote = {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.},
doi = {10.1038/s41467-020-16755-y},
journal = {Nature Communications},
number = 1,
volume = 11,
place = {United States},
year = {2020},
month = {6}
}

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