CD8+ T cell recognition of polymorphic wild-type sequence p53(65-73) peptides in squamous cell carcinoma of the head and neck.
The TP53 tumor suppressor gene contains a well-studied polymorphism that encodes either proline (P) or arginine (R) at codon 72, and over half of the world's population is homozygous for R at this codon. The wild-type sequence (wt) p53 peptide, p53(65-73), has been identified as a CD8+ T cell-defined tumor antigen for use in broadly applicable cancer vaccines. However, depending on the TP53 codon 72 polymorphism of the recipient, the induced responses to the peptides incorporating R (p53(72R)) or P (p53(72P)) can be "self" or "non-self." Thus, we sought to determine which wt p53(65-73) peptide should be used in wt p53-based cancer vaccines. Despite similar predicted HLA-A2-binding affinities, the p53(72P) peptide was more efficient than the p53(72R) peptide in HLA-A2 stabilization assays. In vitro stimulation (IVS) of CD8+ T cells obtained from healthy HLA-A2(+) donors with these two peptides led to the generation of CD8+ T cell effectors in one-third of the samples tested, at a frequency similar to the responsiveness to other wt p53 peptides. Interestingly, regardless of their p53 codon 72 genotype, CD8+ T cells stimulated with either p53(72P) or p53(72R) peptide were cross-reactive against T2 cells pulsed with either peptide, as well as HLA-A2(+) head and neck cancer (HNC) cell lines presenting p53(72P) and/or p53(72R) peptides for T cell recognition. Therefore, the cross-reactivity of CD8+ T cells for the polymorphic wt p53(65-73) peptides, irrespective of their p53 codon 72 polymorphism, suggests that employing either peptide in wt p53-based vaccines can result in efficient targeting of this epitope.
Andrade Filho
Pedro A
PA
Department of Otolaryngology, University of Pittsburgh Medical Center and Cancer Institute, Pittsburgh, USA.
Ito
Daisuke
D
Deleo
Albert B
AB
Ferris
Robert L
RL
D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000276:immunology*; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000276:immunology; D005838:Genotype; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000276:immunology*; D006801:Humans; D010455:Peptides / Q000235:genetics / Q000494:pharmacology; D011110:Polymorphism, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000276:immunology* / Q000494:pharmacology
D010455:Peptides; D016159:Tumor Suppressor Protein p53