title: Peptides derived from human insulin-like growth factor-II mRNA binding protein 3 can induce human leukocyte antigen-A2-restricted cytotoxic T lymphocytes reactive to cancer cells.
abstract: Insulin-like growth factor-II mRNA binding protein 3 (IMP-3) is an oncofetal protein expressed in various malignancies including lung cancer. This study aimed to identify immunogenic peptides derived from IMP-3 that can induce tumor-reactive and human leukocyte antigen (HLA)-A2 (A*02:01)-restricted cytotoxic T lymphocytes (CTL) for lung cancer immunotherapy. Forty human IMP-3-derived peptides predicted to bind to HLA-A2 were analyzed to determine their capacity to induce HLA-A2-restricted T cells in HLA-A2.1 (HHD) transgenic mice (Tgm). We found that three IMP-3 peptides primed HLA-A2-restricted CTL in the HLA-A2.1 Tgm. Among them, human CTL lines reactive to IMP-3 (515) NLSSAEVVV(523) were reproducibly established from HLA-A2-positive healthy donors and lung cancer patients. On the other hand, IMP-3 (199) RLLVPTQFV(207) reproducibly induced IMP-3-specific and HLA-A2-restricted CTL from healthy donors, but did not sensitize CTL in the HLA-A2.1 Tgm. Importantly, these two IMP-3 peptide-specific CTL generated from healthy donors and cancer patients effectively killed the cancer cells naturally expressing both IMP-3 and HLA-A2. Cytotoxicity was significantly inhibited by anti-HLA class I and anti-HLA-A2 monoclonal antibodies, but not by the anti-HLA-class II monoclonal antibody. In addition, natural processing of these two epitopes derived from the IMP-3 protein was confirmed by specific killing of HLA-A2-positive IMP-3-transfectants but not the parental IMP-negative cell line by peptide-induced CTL. This suggests that these two IMP-3-derived peptides represent highly immunogenic CTL epitopes that may be attractive targets 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: Michiko
authors.initials: M
authors.lastname: Harao
authors.forename: Satoru
authors.initials: S
authors.lastname: Senju
authors.forename: Katsunori
authors.initials: K
authors.lastname: Imai
authors.forename: Shinya
authors.initials: S
authors.lastname: Hirata
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: Kentaro
authors.initials: K
authors.lastname: Yoshimoto
authors.forename: Kenji
authors.initials: K
authors.lastname: Shiraishi
authors.forename: Takeshi
authors.initials: T
authors.lastname: Mori
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Nomori
authors.forename: Hirotsugu
authors.initials: H
authors.lastname: Kohrogi
authors.forename: Yasuharu
authors.initials: Y
authors.lastname: Nishimura
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D018984:Epitopes, T-Lymphocyte; D015789:HLA-A2 Antigen / Q000276:immunology*; D006801:Humans; D008175:Lung Neoplasms / Q000276:immunology; D051379:Mice; D009369:Neoplasms / Q000276:immunology*; D010446:Peptide Fragments / Q000276:immunology*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
chemical_list: D018984:Epitopes, T-Lymphocyte; D015789:HLA-A2 Antigen; C498780:IGF2BP3 protein, human; D010446:Peptide Fragments; D016601:RNA-Binding Proteins