title: A conserved E7-derived cytotoxic T lymphocyte epitope expressed on human papillomavirus 16-transformed HLA-A2+ epithelial cancers.
abstract: Human Papillomavirus 16 (HPV-16) has been identified as the causative agent of 50% of cervical cancers and many other HPV-associated tumors. The transforming potential/tumor maintenance capacity of this high risk HPV is mediated by two viral oncoproteins, E6 and E7, making them attractive targets for therapeutic vaccines. Of 21 E6 and E7 peptides computed to bind HLA-A*0201, 10 were confirmed through TAP-deficient T2 cell HLA stabilization assay. Those scoring positive were investigated to ascertain which were naturally processed and presented by surface HLA molecules for CTL recognition. Because IFNγ ELISpot frequencies from healthy HPV-exposed blood donors against HLA-A*0201-binding peptides were unable to identify specificities for tumor targeting, their physical presence among peptides eluted from HPV-16-transformed epithelial tumor HLA-A*0201 immunoprecipitates was analyzed by MS(3) Poisson detection mass spectrometry. Only one epitope (E7(11-19)) highly conserved among HPV-16 strains was detected. This 9-mer serves to direct cytolysis by T cell lines, whereas a related 10-mer (E7(11-20)), previously used as a vaccine candidate, was neither detected by MS(3) on HPV-transformed tumor cells nor effectively recognized by 9-mer specific CTL. These data underscore the importance of precisely defining CTL epitopes on tumor cells and offer a paradigm for T cell-based vaccine design.
authors.affiliation: Cancer Vaccine Center, Laboratory of Immunobiology, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Angelika B
authors.initials: AB
authors.lastname: Riemer
authors.forename: Derin B
authors.initials: DB
authors.lastname: Keskin
authors.forename: Guanglan
authors.initials: G
authors.lastname: Zhang
authors.forename: Maris
authors.initials: M
authors.lastname: Handley
authors.forename: Karen S
authors.initials: KS
authors.lastname: Anderson
authors.forename: Vladimir
authors.initials: V
authors.lastname: Brusic
authors.forename: Bruce
authors.initials: B
authors.lastname: Reinhold
authors.forename: Ellis L
authors.initials: EL
authors.lastname: Reinherz
mesh_terms: D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D019295:Computational Biology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology / Q000378:metabolism*; D015234:HLA-A Antigens / Q000276:immunology / Q000378:metabolism; D015789:HLA-A2 Antigen / Q000276:immunology / Q000378:metabolism*; D052162:Human papillomavirus 16 / Q000235:genetics / Q000276:immunology*; D006801:Humans; D047468:Immunoprecipitation; D007371:Interferon-gamma / Q000378:metabolism; D013058:Mass Spectrometry; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000276:immunology; D050725:Papillomavirus E7 Proteins / Q000235:genetics / Q000276:immunology; D010455:Peptides / Q000276:immunology / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism*; D014161:Transduction, Genetic
chemical_list: C068651:E6 protein, Human papillomavirus type 16; D018984:Epitopes, T-Lymphocyte; D015234:HLA-A Antigens; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D010455:Peptides; D012097:Repressor Proteins; C059731:oncogene protein E7, Human papillomavirus type 16; D007371:Interferon-gamma