title: Identification of an HLA-A*0201-restricted cytotoxic T lymphocyte epitope from the lung carcinoma antigen, Lengsin.
abstract: Lengsin is an eye lens protein with a glutamine synthetase domain. We previously identified this protein as a lung carcinoma antigen through cDNA microarray analysis. Lengsin protein is overexpressed irrespective of the histological type of lung carcinoma, but not in normal tissues other than the lens. Therefore, to significantly extend the use of Lengsin-based T-cell immunotherapies for the treatment of patients with lung carcinoma, we searched for HLA-A*0201-restricted epitopes from this protein by screening predicted Lengsin-derived candidate peptides for the induction of tumor-reactive CTLs. Four Lengsin-derived peptides were selected by computerized algorithm based on a permissive HLA-A*0201 binding motif, and were used to immunize HLA-A*0201 transgenic (HHD) mice. Two of the immunizing peptides, Lengsin(206-215)(FIYDFCIFGV) and Lengsin(270-279)(FLPEFGISSA), induced peptide-specific cytotoxic T lymphocytes (CTLs) in HHD mice, and thus were used to stimulate human peripheral blood lymphocytes in vitro. Lengsin(206-215) and Lengsin (270-279) also induced human peptide-specific CTLs, and we were able to generate Lengsin(206-215)- and Lengsin(270-279)-specific CTL clones. The Lengsin(270-279)-specific CTL clone specifically recognized peptide-pulsed T2 cells, COS-7 cells expressing HLA-A*0201 and Lengsin, and HLA-A*0201+/Lengsin+ lung carcinoma cells in an HLA-A*0201-restricted manner. On the other hand, the Lengsin(206-215)-specific CTL clone failed to recognize HLA-A*0201+/Lengsin+ target cells in the absence of cognate peptide. These results suggest that Lengsin(270-279) is naturally processed and presented by HLA-A*0201 molecules on the surface of lung carcinoma cells and may be a new target for antigen-specific T-cell immunotherapy against lung cancer.
authors.affiliation: Section for Cancer Immunotherapy, Investigative Treatment Division, Research Center for Innovative Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba 277-8577, Japan.
authors.forename: Munehide
authors.initials: M
authors.lastname: Nakatsugawa
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Horie
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Yoshikawa
authors.forename: Manami
authors.initials: M
authors.lastname: Shimomura
authors.forename: Yamato
authors.initials: Y
authors.lastname: Kikuchi
authors.forename: Noriko
authors.initials: N
authors.lastname: Sakemura
authors.forename: Shiro
authors.initials: S
authors.lastname: Suzuki
authors.forename: Daisuke
authors.initials: D
authors.lastname: Nobuoka
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Hirohashi
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Torigoe
authors.forename: Kenji
authors.initials: K
authors.lastname: Harada
authors.forename: Hideo
authors.initials: H
authors.lastname: Takasu
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Sato
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Nakatsura
mesh_terms: D000230:Adenocarcinoma / Q000276:immunology*; D000077192:Adenocarcinoma of Lung; D000465:Algorithms; D000818:Animals; D019556:COS Cells; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D005974:Glutamate-Ammonia Ligase / Q000276:immunology*; D015789:HLA-A2 Antigen / Q000276:immunology*; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D008175:Lung Neoplasms / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010455:Peptides / Q000276:immunology; D011485:Protein Binding; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
chemical_list: D018984:Epitopes, T-Lymphocyte; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D010455:Peptides; D005974:Glutamate-Ammonia Ligase; C507977:LGSN protein, human