Generation of T cells specific for the wild-type sequence p53(264-272) peptide in cancer patients: Implications for immunoselection of epitope loss variants

Alterations in the p53 gene occur frequently and can lead to accumulation o f p53 protein in squamous cell carcinomas of the head and neck (SCCHN), Sin ce accumulation of p53 is associated with enhanced presentation of wild-typ e sequence (wt) p53 peptides to immune cells, the development of pan vaccin es against SCCHN has focused on,vt p53 epitopes, We used the HLA-A2.1-restr icted wt p53(264-272) epitope to generate CTL from circulating precursor T cells of HLA-A2.1(+) healthy donors and patients with SCCHN, Autologous pep tide-pulsed dendritic cells were used for in vitro sensitization, CTL speci fic 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 CT L 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 presenti ng the epitope, Paradoxically, none of the tumors in the three patients who generated CTL could adequately present the epitope; two had a nt p53 genot ype and no p53 protein accumulation, while the third tumor expressed a poin t 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 tha t accumulated altered p53 and potentially could present the p53(264-272) ep itope. 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 expressin g this epitope and in immunoselection of epitope-loss tumor cells, Immunose lection of tumors that become resistant to anti-p53 immune responses has im portant implications for future p53-based vaccination strategies.