title: Prognostic impact and immunogenicity of a novel osteosarcoma antigen, papillomavirus binding factor, in patients with osteosarcoma.
abstract: To develop peptide-based immunotherapy for osteosarcoma, we previously identified papillomavirus binding factor (PBF) as a cytotoxic T lymphocytes (CTL)-defined osteosarcoma antigen in the context of human leukocyte antigen (HLA)-B55. In the present study, we analyzed the distribution profile of PBF in 83 biopsy specimens of osteosarcomas and also the prognostic impact of PBF expression in 78 patients with osteosarcoma who had completed the standard treatment protocols. Next, we determined the antigenic peptides from PBF that react with peripheral T lymphocytes of HLA-A24(+) patients with osteosarcoma. Immunohistochemical analysis revealed that 92% of biopsy specimens of osteosarcoma expressed PBF. PBF-positive osteosarcoma conferred significantly poorer prognosis than those with negative expression of PBF (P = 0.025). In accordance with the Bioinformatics and Molecular Analysis Section score, we synthesized 10 peptides from the PBF sequence. Subsequent screening with an HLA class I stabilization assay revealed that peptide PBF A24.2 had the highest affinity to HLA-A24. CD8(+) T cells reacting with a PBF A24.2 peptide were detected in eight of nine HLA-A24-positive patients with osteosarcoma at the frequency from 5 x 10(-7) to 7 x 10(-6) using limiting dilution/mixed lymphocyte peptide culture followed by tetramer-based frequency analysis. PBF A24.2 peptide induced CTL lines from an HLA-A24-positive patient, which specifically killed an osteosarcoma cell line that expresses both PBF and HLA-A24. These findings suggested prognostic significance and immunodominancy of PBF in patients with osteosarcoma. PBF is the candidate target for immunotherapy in patients with osteosarcoma.
authors.affiliation: Department of Orthopaedic Surgery, Sapporo Medical Unviersity School of Medicine, South-1, West-16, Chuo-ku, Sapporo, Japan.
authors.forename: Tomohide
authors.initials: T
authors.lastname: Tsukahara
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kawaguchi
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Torigoe
authors.forename: Shigeharu
authors.initials: S
authors.lastname: Kimura
authors.forename: Masaki
authors.initials: M
authors.lastname: Murase
authors.forename: Shingo
authors.initials: S
authors.lastname: Ichimiya
authors.forename: Takuro
authors.initials: T
authors.lastname: Wada
authors.forename: Mitsunori
authors.initials: M
authors.lastname: Kaya
authors.forename: Satoshi
authors.initials: S
authors.lastname: Nagoya
authors.forename: Takeshi
authors.initials: T
authors.lastname: Ishii
authors.forename: Shin-ichiro
authors.initials: S
authors.lastname: Tatezaki
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Yamashita
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Sato
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D000951:Antigens, Neoplasm / Q000276:immunology* / Q000378:metabolism; D001859:Bone Neoplasms / Q000175:diagnosis* / Q000276:immunology* / Q000378:metabolism; D002648:Child; D004268:DNA-Binding Proteins / Q000276:immunology* / Q000378:metabolism; D005260:Female; D015234:HLA-A Antigens / Q000235:genetics / Q000276:immunology; D059871:HLA-A24 Antigen; D006801:Humans; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D012516:Osteosarcoma / Q000175:diagnosis* / Q000276:immunology* / Q000378:metabolism; D011379:Prognosis; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014157:Transcription Factors / Q000276:immunology* / Q000378:metabolism
chemical_list: D000951:Antigens, Neoplasm; D004268:DNA-Binding Proteins; D015234:HLA-A Antigens; D059871:HLA-A24 Antigen; D014157:Transcription Factors; C484332:ZNF395 protein, human