title: Immunological characterization of missense mutations occurring within cytotoxic T cell-defined p53 epitopes in HLA-A*0201+ squamous cell carcinomas of the head and neck.
abstract: Previous analyses of p53 in 40 HLA-A*0201(HLA-A2)(+) squamous cell carcinomas of the head and neck (SCCHN) indicated that 6/13 p53 missense mutations that were detected, S149C, T150R, V157F, Y220C, Y220H and E271K, occurred within HLA-A2-restricted cytotoxic T lymphocyte (CTL)-defined p53 epitopes. Of the 6, the p53 S149C, Y220C and Y220H peptides were immunogenic. Anti-p53 mutant S149C and Y220H effector cells cross-reacted against the parental wild type sequence (wt) p53 peptides, whereas anti-p53 Y220C effector cells were specific for the mutant peptide, p53 Y220C cDNA-transfected HLA-A2(+) SaOS cells, and an HLA-A2(+) SCCHN cell line naturally expressing the mutation. These results indicate that the p53 Y220C mutation can be processed and presented for CD8(+) T cell recognition. Furthermore, using an autologous PBMC/tumor system, anti-p53 Y220C peptide-effector cells recognizing the autologous tumor could also be generated. Our analysis of p53 in 10 additional HLA-A2(+) SCCHN tumors detected the p53 Y220C in 2/10 tumors raising the overall frequency of the p53 Y220C mutation to 6/50 (12%) HLA-A2(+) SCCHN tumors. In contrast, independent of their HLA class I genotypes, the p53 Y220C mutation frequency for all human tumors analyzed to date is approximately 1.5%. This unexpectedly high frequency of the p53 Y220C mutation in HLA-A2(+) SCCHN suggests that vaccines targeting this mutation would not only be expected to induce robust anti-tumor immune responses in HLA-A2(+) subjects, but also be more widely applicable than previously envisioned for any given p53 missense mutation.
authors.affiliation: Division of Basic Research, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Ito
authors.forename: Carmen
authors.initials: C
authors.lastname: Visus
authors.forename: Thomas K
authors.initials: TK
authors.lastname: Hoffmann
authors.forename: Vera
authors.initials: V
authors.lastname: Balz
authors.forename: Henning
authors.initials: H
authors.lastname: Bier
authors.forename: Ettore
authors.initials: E
authors.lastname: Appella
authors.forename: Theresa L
authors.initials: TL
authors.lastname: Whiteside
authors.forename: Robert L
authors.initials: RL
authors.lastname: Ferris
authors.forename: Albert B
authors.initials: AB
authors.lastname: DeLeo
mesh_terms: D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000276:immunology / Q000473:pathology; D045744:Cell Line, Tumor; D003601:Cytotoxicity Tests, Immunologic; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D000939:Epitopes / Q000235:genetics* / Q000276:immunology; D015870:Gene Expression; D015234:HLA-A Antigens / Q000235:genetics / Q000276:immunology*; D015789:HLA-A2 Antigen; D006258:Head and Neck Neoplasms / Q000235:genetics / Q000276:immunology / Q000473:pathology; D006801:Humans; D020125:Mutation, Missense; D010455:Peptides / Q000235:genetics / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000235:genetics* / Q000276:immunology
chemical_list: D000939:Epitopes; D015234:HLA-A Antigens; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D010455:Peptides; D016159:Tumor Suppressor Protein p53