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A Wild-type Sequence p53 Peptide Presented by HLA-A24 Induces Cytotoxic T Lymphocytes that Recognize Squamous Cell Carcinomas of the Head and Neck¹

Department of Otolaryngology [M. E., K. C., F. K., A. O.] and Division of Viral Immunology [ Y. Sob., M. T.], Center for AIDS Research, Kumamoto University School of Medicine, Kumamoto 860-8556, Japan; National Cancer Institute, NIH, Bethesda, Maryland 20892 [Y. Son., E. A.]; and Division of Basic Research, University of Pittsburgh Cancer Institute [T. L. W., A. B. D.] and Departments of Otolaryngology [T. L. W.] and Pathology [T. L. W.], School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15213

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- 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.

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