HLA-A2-restricted CTL epitopes of a novel lung cancer-associated cancer testis antigen, cell division cycle associated 1, can induce tumor-reactive CTL.
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.
Harao
Michiko
M
Department of Immunogenetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
Hirata
Shinya
S
Irie
Atsushi
A
Senju
Satoru
S
Nakatsura
Tetsuya
T
Komori
Hiroyuki
H
Ikuta
Yoshiaki
Y
Yokomine
Kazunori
K
Imai
Katsunori
K
Inoue
Mitsuhiro
M
Harada
Kumiko
K
Mori
Takeshi
T
Tsunoda
Takuya
T
Nakatsuru
Shuichi
S
Daigo
Yataro
Y
Nomori
Hiroaki
H
Nakamura
Yusuke
Y
Baba
Hideo
H
Nishimura
Yasuharu
Y
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
D000951:Antigens, Neoplasm; D018797:Cell Cycle Proteins; D018984:Epitopes, T-Lymphocyte; D015789:HLA-A2 Antigen; C490197:NUF2 protein, human; D012333:RNA, Messenger