title: Generation of T cells specific for the wild-type sequence p53(264-272) peptide in cancer patients: implications for immunoselection of epitope loss variants.
abstract: Alterations in the p53 gene occur frequently and can lead to accumulation of p53 protein in squamous cell carcinomas of the head and neck (SCCHN). Since accumulation of p53 is associated with enhanced presentation of wild-type sequence (wt) p53 peptides to immune cells, the development of pan vaccines against SCCHN has focused on wt p53 epitopes. We used the HLA-A2.1-restricted wt p53(264-272) epitope to generate CTL from circulating precursor T cells of HLA-A2.1(+) healthy donors and patients with SCCHN. Autologous peptide-pulsed dendritic cells were used for in vitro sensitization. CTL specific for the wt p53(264-272) peptide were generated from PBMC obtained from two of seven normal donors and three of seven patients with SCCHN. These CTL were HLA class I restricted and responded to T2 cells pulsed with p53(264-272) peptide as well as HLA-A2-matched SCCHN cell lines naturally presenting the epitope. Paradoxically, none of the tumors in the three patients who generated CTL could adequately present the epitope; two had a wt p53 genotype and no p53 protein accumulation, while the third tumor expressed a point mutation (R to H) in codon 273 that prevents presentation of the p53(264-272) epitope. In contrast, patients who did not generate CTL had tumors that accumulated altered p53 and potentially could present the p53(264-272) epitope. These findings suggest that in vivo, CTL specific for the wt p53(264-272) peptide might play a role in the elimination of tumor cells expressing this epitope and in immunoselection of epitope-loss tumor cells. Immunoselection of tumors that become resistant to anti-p53 immune responses has important implications for future p53-based vaccination strategies.
authors.affiliation: University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
authors.forename: T K
authors.initials: TK
authors.lastname: Hoffmann
authors.forename: K
authors.initials: K
authors.lastname: Nakano
authors.forename: E M
authors.initials: EM
authors.lastname: Elder
authors.forename: G
authors.initials: G
authors.lastname: Dworacki
authors.forename: S D
authors.initials: SD
authors.lastname: Finkelstein
authors.forename: E
authors.initials: E
authors.lastname: Appella
authors.forename: T L
authors.initials: TL
authors.lastname: Whiteside
authors.forename: A B
authors.initials: AB
authors.lastname: DeLeo
mesh_terms: D001323:Autoantibodies / Q000097:blood; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000276:immunology*; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D004252:DNA Mutational Analysis; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D005434:Flow Cytometry; D014644:Genetic Variation / Q000276:immunology; D015789:HLA-A2 Antigen / Q000276:immunology / Q000378:metabolism; D006258:Head and Neck Neoplasms / Q000235:genetics / Q000276:immunology*; D006801:Humans; D016056:Immunodominant Epitopes / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000235:genetics*; D010446:Peptide Fragments / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D013194:Staining and Labeling; D016176:T-Lymphocyte Subsets / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
chemical_list: D001323:Autoantibodies; D018984:Epitopes, T-Lymphocyte; D015789:HLA-A2 Antigen; D016056:Immunodominant Epitopes; D010446:Peptide Fragments; D016159:Tumor Suppressor Protein p53