title: A novel tumor-associated antigen, cell division cycle 45-like can induce cytotoxic T-lymphocytes reactive to tumor cells.
abstract: The present study attempted to identify a useful tumor-associated antigen (TAA) for lung cancer immunotherapy and potential immunogenic peptides derived from the TAA. We focused on cell division cycle 45-like (CDC45L), which has a critical role in the initiation and elongation steps of DNA replication, as a novel candidate TAA for immunotherapy based on a genome-wide cDNA microarray analysis of lung cancer. The CDC45L was overexpressed in the majority of lung cancer tissues, but not in the adjacent non-cancerous tissues or in many normal adult tissues. We examined the in vitro and in vivo anti-tumor effects of cytotoxic T-lymphocytes (CTL) specific to CDC45L-derived peptides induced from HLA-A24 (A*24:02)-positive donors. We identified three CDC45L-derived peptides that could reproducibly induce CDC45L-specific and HLA-A24-restricted CTL from both healthy donors and lung cancer patients. The CTL could effectively lyse lung cancer cells that endogenously expressed both CDC45L and HLA-A24. In addition, we found that CDC45L (556) KFLDALISL(564) was eminent in that it induced not only HLA-A24 but also HLA-A2 (A*02:01)-restricted antigen specific CTL. Furthermore, the adoptive transfer of the CDC45L-specific CTL inhibited the growth of human cancer cells engrafted into immunocompromised mice. These results suggest that these three CDC45L-derived peptides are highly immunogenic epitopes and CDC45L is a novel TAA that might be a useful target for lung cancer immunotherapy.
authors.affiliation: Department of Immunogenetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Tomita
authors.forename: Katsunori
authors.initials: K
authors.lastname: Imai
authors.forename: Satoru
authors.initials: S
authors.lastname: Senju
authors.forename: Atsushi
authors.initials: A
authors.lastname: Irie
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Inoue
authors.forename: Yuki
authors.initials: Y
authors.lastname: Hayashida
authors.forename: Kenji
authors.initials: K
authors.lastname: Shiraishi
authors.forename: Takeshi
authors.initials: T
authors.lastname: Mori
authors.forename: Yataro
authors.initials: Y
authors.lastname: Daigo
authors.forename: Takuya
authors.initials: T
authors.lastname: Tsunoda
authors.forename: Takaaki
authors.initials: T
authors.lastname: Ito
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Nomori
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Hirotsugu
authors.initials: H
authors.lastname: Kohrogi
authors.forename: Yasuharu
authors.initials: Y
authors.lastname: Nishimura
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015152:Blotting, Northern; D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D000939:Epitopes / Q000276:immunology*; D020869:Gene Expression Profiling; D015234:HLA-A Antigens / Q000276:immunology* / Q000378:metabolism; D059871:HLA-A24 Antigen; D006801:Humans; D007124:Immunoenzyme Techniques; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009369:Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000628:therapy*; D020411:Oligonucleotide Array Sequence Analysis; D010446:Peptide Fragments / Q000276:immunology* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014407:Tumor Cells, Cultured
chemical_list: D014408:Biomarkers, Tumor; C113571:CDC45 protein, human; D018797:Cell Cycle Proteins; D000939:Epitopes; D015234:HLA-A Antigens; D059871:HLA-A24 Antigen; D010446:Peptide Fragments; D012333:RNA, Messenger