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Generation of T Cells Specific for the Wild-Type Sequence p53_264–272 Peptide in Cancer Patients: Implications for Immunoselection of Epitope Loss Variants¹

Thomas K. Hoffmann^*, Koji Nakano^*, Elaine M. Elder^*, Grzegorz Dworacki^*, Sydney D. Finkelstein, Ettore Appella, Theresa L. Whiteside^2,*,, and Albert B. DeLeo^*,

^* University of Pittsburgh Cancer Institute and Departments of Pathology and Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213; and National Cancer Institute, Bethesda, MD 20892

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.

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