p53 as an immunotherapeutic target in head and neck cancer.

摘要

Squamous cell carcinomas of the head and neck (HNSCCs) are characterized by a high frequency of mutations in the p53 gene often leading to p53 protein accumulation. 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 HNSCC has focused on wt p53 epitopes. We used the HLA-A2.1-restricted wt p53 264-272 epitope pulsed on autologous dendritic cells to generate cytotoxic T lymphocytes (CTLs) ex vivo from circulating precursor T cells of HLA-A2.1+ patients with HNSCC. CTLs specific for the wt p53 264-272 peptide were generated from leukocytes obtained from a cohort of patients with HNSCC (group A). Paradoxically, none of those patients had tumors which adequately presented the epitope, i.e. accumulated p53. In contrast, patients who did not generate CTLs (group B) had tumors which accumulated altered p53 and potentially could present the p53 264-272 epitope. When p53 264-272-specific T cells were directly enumerated in the peripheral circulation of patients with HNSCC using tetrameric p53 264-272/HLA-A2.1 complexes by multicolor flow cytometry, group A had high and group B low percentages of tetramer+ CD3+ CD8+ T cells. These findings suggested that in vivo p53-specific CTLs in group A might play a role in the elimination of tumor cells expressing the p53 264-272 epitope ('immunoselection'), leading to the outgrowth of 'epitope loss' tumor cells. On the other hand, precursor CTLs specific for the wt p53 264-272 peptide in group B are unresponsive to the p53 antigen. Unresponsiveness of CTLs specific for the wt p53264-272 peptide detected in group B could be reversed by using more immunogenic variant peptides of the p53 264-272 epitope. In vivo, immunoselection of tumors which become resistant to anti-p53 immune responses has important implications for future p53-based vaccination strategies. It calls for modified approaches, in which altered peptide variants of the wt sequence p53 264-272 epitopeare used in a vaccine in order to overcome unresponsiveness of T lymphocytes to the native epitope.