title: A wild-type sequence p53 peptide presented by HLA-A24 induces cytotoxic T lymphocytes that recognize squamous cell carcinomas of the head and neck.
abstract: Evidence has accumulated indicating that HLA-A2-restricted CTLs specific for human wild-type sequence p53 epitopes lyse tumor cells expressing mutant p53. To explore the possibility that wild-type sequence p53 peptides could also be used in vaccines for patients expressing HLA-A24 antigen, another frequent HLA class I allele, we investigated the induction of HLA-A24-restricted p53-specific CTLs from the peripheral blood lymphocytes of normal donors. Of six p53-derived peptides possessing an HLA-A24 binding motif, the p53 peptide 125-134 (p53(125-134)) was found to have a high binding capacity and induced peptide-specific CTLs from peripheral blood mononuclear cells, using peptide-pulsed autologous dendritic cells and subsequent cultivation with cytokines interleukin 2 and interleukin 7. Bulk CTL populations lysed peptide-pulsed HLA-A24+ targets as well as HLA-A24+ squamous cell carcinoma of the head and neck (SCCHN) cell lines. However, IFN-gamma pretreatment of HLA-A24+ SCCHN cell lines was necessary for lysis, suggesting that a ligand density higher than that normally expressed by tumor cells is required for these CTLs to mediate lysis. Moreover, a cloned CTL, designated TH#99, isolated from the bulk population by limiting dilution, lysed HLA-A24+ SCCHN targets more efficiently than the bulk CTL population. Lysis was inhibited by anti-HLA class I monoclonal antibody but not by anti-HLA-DR monoclonal antibody. These results indicate that HLA-A24-restricted CTLs recognizing the wild-type sequence p53(125-134) can be generated using autologous dendritic cells from precursors present in peripheral blood lymphocytes obtained from normal HLA-A24+ donors. This finding suggests that vaccine strategies targeting wild-type sequence p53 epitopes can be extended to a wider range of cancer patients.
authors.affiliation: Department of Otolaryngology, Center for AIDS Research, Kumamoto University School of Medicine, Japan. eura@gpo.kumamoto-u.ac.jp
authors.forename: M
authors.initials: M
authors.lastname: Eura
authors.forename: K
authors.initials: K
authors.lastname: Chikamatsu
authors.forename: F
authors.initials: F
authors.lastname: Katsura
authors.forename: A
authors.initials: A
authors.lastname: Obata
authors.forename: Y
authors.initials: Y
authors.lastname: Sobao
authors.forename: M
authors.initials: M
authors.lastname: Takiguchi
authors.forename: Y
authors.initials: Y
authors.lastname: Song
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: D000595:Amino Acid Sequence; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001667:Binding, Competitive; D002294:Carcinoma, Squamous Cell / Q000276:immunology* / Q000473:pathology; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D015234:HLA-A Antigens / Q000276:immunology / Q000378:metabolism*; D006258:Head and Neck Neoplasms / Q000276:immunology* / Q000473:pathology; D006801:Humans; D020014:K562 Cells; D009154:Mutation; D009842:Oligopeptides / Q000276:immunology / Q000378:metabolism; D011485:Protein Binding; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D015234:HLA-A Antigens; D009842:Oligopeptides; D016159:Tumor Suppressor Protein p53