9OBF

Crystal structure of HLA*02:01 with the 11-mer TP53 peptide GLAPPQHLIRV

Summary for 9OBF

• Entry DOI: 10.2210/pdb9obf/pdb
• Descriptor: MHC class I antigen, Beta-2-microglobulin, Peptide from Cellular tumor antigen p53, ... (5 entities in total)
• Functional Keywords: hla-a*02:01, tp53, immune system
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 6
• Total formula weight: 91259.65

Authors

Tan, K.,Mallis, R.J.,Reinherz, E.L. (deposition date: 2025-04-22, release date: 2026-06-24, Last modification date: 2026-10-28)

Primary citation

Haratani, K.,Reinhold, B.,Duke-Cohan, J.S.,Fahey, C.G.,Tan, K.,Mallis, R.J.,Gusev, A.,Kehl, K.L.,Luo, J.,Karmazyn, A.,Holliday, E.L.,Masi, D.J.,Zienkiewicz, K.J.,Hennessey, C.J.,Blasco, R.B.,Thai, T.C.,Gibbons, G.M.,Kivlehan, S.,Lizotte, P.,Paweletz, C.P.,Aguirre, A.J.,Ligon, K.L.,Chiarle, R.,Lang, M.J.,Barbie, D.A.,Reinherz, E.L.
Cancers modulate processing and presentation of p53 neoantigens to evade T cell detection.
Immunity, 59:2789-, 2026

PubMed Abstract: TP53 mutations occur early in malignant transformation as truncal events in tumor evolution and are therefore generally present in all descendant tumor cells, creating an immunological vulnerability. Here, we examined the immunogenicity and antigenicity of p53 neoantigens emerging from these truncal mutations. Comprehensive immunopeptidomics revealed that hotspot mutations in human tumors preferentially localize to p53 regions resistant to antigen processing, thereby avoiding display altogether. Moreover, for neoantigens presentable by HLA-A02:01 or HLA-B07:02 and structurally divergent from corresponding wild-type p53 peptide-HLA complexes, clinical tumors commonly lacked the relevant presenting HLA allele. Tumor cells further resisted T cell killing through increased activity of the aminopeptidase ERAP1, preventing display of high-affinity HLA-A02:01 complexes containing an immunogenic p53-derived 11-mer, or by expressing low-affinity HLA-A02:01 complexes containing a p53-derived 9-mer with poor antigenicity despite high-quality human TCRs. These findings define mechanisms by which tumors restrict targetable truncal neoantigen display and suggest immunopeptidome shift strategies to circumvent immune escape.

PubMed: 42753739
DOI: 10.1016/j.immuni.2026.08.011

Experimental method

X-RAY DIFFRACTION (3.25 Å)