title: HLA-A2-restricted CTL epitopes of a novel lung cancer-associated cancer testis antigen, cell division cycle associated 1, can induce tumor-reactive CTL.
abstract: Toward the development of a novel cancer immunotherapy, we have previously identified several tumor-associated antigens (TAAs) and the epitopes recognized by human histocompatibility leukocyte (HLA)-A2/A24-restricted cytotoxic T lymphocyte (CTL). In this study, we tried to identify a TAA of lung cancer (LC) and its HLA-A2 restricted CTL epitopes to provide a target antigen useful for cancer immunotherapy of LC. We identified a novel cancer testis antigen, cell division cycle associated gene 1 (CDCA1), overexpressed in nonsmall cell LC using a cDNA microarray analysis. The expression levels of CDCA1 were also increased in the majority of small cell LC, cholangiocellular cancer, urinary bladder cancer and renal cell cancers. We used HLA-A2.1 transgenic mice to identify the HLA-A2 (A*0201)-restricted CDCA1 epitopes recognized by mouse CTL, and we investigated whether these peptides could induce CDCA1-reactive CTLs from the peripheral blood mononuclear cells (PBMCs) of HLA-A2-positive donors and a NSCLC patient. Consequently, we found that the CDCA1(65-73) (YMMPVNSEV) peptide and CDCA1(351-359) (KLATAQFKI) peptide could induce peptide-reactive CTLs in HLA-A2.1 transgenic mice. In HLA-A2(+) donors, in vitro stimulation of PBMC with these peptides could induce peptide-reactive CTLs which killed tumor cell lines endogenously expressing both HLA-A2 and CDCA1. As a result, CDCA1 is a novel cancer-testis antigen overexpressed in LC, cholangiocellular cancer, urinary bladder cancer and renal cell cancers, and CDCA1 may therefore be an ideal TAA useful for the diagnosis and immunotherapy of these cancers.
authors.affiliation: Department of Immunogenetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Michiko
authors.initials: M
authors.lastname: Harao
authors.forename: Shinya
authors.initials: S
authors.lastname: Hirata
authors.forename: Atsushi
authors.initials: A
authors.lastname: Irie
authors.forename: Satoru
authors.initials: S
authors.lastname: Senju
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Nakatsura
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Komori
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Ikuta
authors.forename: Kazunori
authors.initials: K
authors.lastname: Yokomine
authors.forename: Katsunori
authors.initials: K
authors.lastname: Imai
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Inoue
authors.forename: Kumiko
authors.initials: K
authors.lastname: Harada
authors.forename: Takeshi
authors.initials: T
authors.lastname: Mori
authors.forename: Takuya
authors.initials: T
authors.lastname: Tsunoda
authors.forename: Shuichi
authors.initials: S
authors.lastname: Nakatsuru
authors.forename: Yataro
authors.initials: Y
authors.lastname: Daigo
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Nomori
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Hideo
authors.initials: H
authors.lastname: Baba
authors.forename: Yasuharu
authors.initials: Y
authors.lastname: Nishimura
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology*; D018797:Cell Cycle Proteins / Q000276:immunology / Q000378:metabolism*; D045744:Cell Line, Tumor; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D005786:Gene Expression Regulation; D015789:HLA-A2 Antigen / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D006262:Health; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000276:immunology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009928:Organ Specificity; D012333:RNA, Messenger / Q000235:genetics; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D013737:Testis / Q000378:metabolism
chemical_list: D000951:Antigens, Neoplasm; D018797:Cell Cycle Proteins; D018984:Epitopes, T-Lymphocyte; D015789:HLA-A2 Antigen; C490197:NUF2 protein, human; D012333:RNA, Messenger