• Open Access

Prognostic impact and immunogenicity of a novel osteosarcoma antigen, papillomavirus binding factor, in patients with osteosarcoma

Authors

  • Tomohide Tsukahara,

    1. Research Fellow of the Japan Society for the Promotion of Science,
    2. Department of Orthopaedic Surgery, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-ku, Sapporo, 060-8543;
    3. Department of Pathology, Sapporo Medical University School of Medicine, South-1, West-17, Chuo-ku, Sapporo, 060-8556;
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  • Satoshi Kawaguchi,

    Corresponding author
    1. Department of Orthopaedic Surgery, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-ku, Sapporo, 060-8543;
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  • Toshihiko Torigoe,

    1. Department of Pathology, Sapporo Medical University School of Medicine, South-1, West-17, Chuo-ku, Sapporo, 060-8556;
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  • Shigeharu Kimura,

    1. Department of Pathology, Sapporo Medical University School of Medicine, South-1, West-17, Chuo-ku, Sapporo, 060-8556;
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  • Masaki Murase,

    1. Department of Orthopaedic Surgery, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-ku, Sapporo, 060-8543;
    2. Department of Pathology, Sapporo Medical University School of Medicine, South-1, West-17, Chuo-ku, Sapporo, 060-8556;
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  • Shingo Ichimiya,

    1. Department of Pathology, Sapporo Medical University School of Medicine, South-1, West-17, Chuo-ku, Sapporo, 060-8556;
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  • Takuro Wada,

    1. Department of Orthopaedic Surgery, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-ku, Sapporo, 060-8543;
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  • Mitsunori Kaya,

    1. Department of Orthopaedic Surgery, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-ku, Sapporo, 060-8543;
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  • Satoshi Nagoya,

    1. Department of Orthopaedic Surgery, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-ku, Sapporo, 060-8543;
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  • Takeshi Ishii,

    1. Division of Orthopaedic Surgery, Chiba Cancer Center, 666-2 Nitona-cho, Chuo-ku, Chiba, 260-8717, Japan
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  • Shin-ichiro Tatezaki,

    1. Division of Orthopaedic Surgery, Chiba Cancer Center, 666-2 Nitona-cho, Chuo-ku, Chiba, 260-8717, Japan
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  • Toshihiko Yamashita,

    1. Department of Orthopaedic Surgery, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-ku, Sapporo, 060-8543;
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  • Noriyuki Sato

    1. Department of Pathology, Sapporo Medical University School of Medicine, South-1, West-17, Chuo-ku, Sapporo, 060-8556;
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  • Grant support: This work was supported by Grants-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan (Grant no. 16209013 to N. Sato), Practical Application Research from the Japan Science and Technology Agency (Grant No. H14-2 to N. Sato), the Ministry of Health, Labor and Welfare (Grant No. H17-Gann-Rinsyo-006 to T. Wada), Postdoctoral Fellowship of the Japan Society for the Promotion of Science (Grant no. 02568 to T. Tsukahara) and Northern Advancement Center for Science and Technology (Grant No. H18-Waka-075 to T. Tsukahara).

To whom correspondence should be addressed. E-mail: kawaguch@sapmed.ac.jp

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 × 10−7 to 7 × 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. (Cancer Sci 2008; 99: 368–375)

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