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

Journal Article · · Nature Communications
 [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)
+ Show Author Affiliations

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.

Research Organization:
Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)
Sponsoring Organization:
NIH; USDOE
OSTI ID:
1633804
Journal Information:
Nature Communications, Journal Name: Nature Communications Journal Issue: 1 Vol. 11; ISSN 2041-1723
Publisher:
Nature Publishing GroupCopyright Statement
Country of Publication:
United States
Language:
ENGLISH

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