title: Identification of CDCA1-derived long peptides bearing both CD4+ and CD8+ T-cell epitopes: CDCA1-specific CD4+ T-cell immunity in cancer patients.
abstract: We recently identified a novel cancer-testis antigen, cell division cycle associated 1 (CDCA1) using genome-wide cDNA microarray analysis, and CDCA1-derived cytotoxic T lymphocyte (CTL)-epitopes. In this study, we attempted to identify CDCA1-derived long peptides (LPs) that induce both CD4+ helper T (Th) cells and CTLs. We combined information from a recently developed computer algorithm predicting HLA class II-binding peptides with CDCA1-derived CTL-epitope sequences presented by HLA-A2 (A*02:01) or HLA-A24 (A*24:02) to select candidate CDCA1-LPs encompassing both Th cell epitopes and CTL-epitopes. We studied the immunogenicity of CDCA1-LPs and the cross-priming potential of LPs bearing CTL-epitopes in both human in vitro and HLA-class I transgenic mice in vivo. Then we analyzed the Th cell response to CDCA1 in head-and-neck cancer (HNC) patients before and after vaccination with a CDCA1-derived CTL-epitope peptide using IFN-γ enzyme-linked immunospot assays. We identified two CDCA1-LPs, CDCA1(39–64)-LP and CDCA1(55–78)-LP, which encompass naturally processed epitopes recognized by Th cells and CTLs. CDCA1-specific CTLs were induced through cross-presentation of CDCA1-LPs in vitro and in vivo. In addition, CDCA1-specific Th cells enhanced induction of CDCA1-specific CTLs. Furthermore, significant frequencies of CDCA1-specific Th cell responses were detected after short-term in vitro stimulation of peripheral blood mononuclear cells (PBMCs) with CDCA1-LPs in HNC patients (CDCA1(39–64)-LP, 74%; CDCA1(55–78)-LP, 68%), but not in healthy donors. These are the first results demonstrating the presence of CDCA1-specific Th cell responses in HNC patients and underline the possible utility of CDCA1-LPs for propagation of both CDCA1-specific Th cells and CTLs.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Tomita
authors.forename: Akira
authors.initials: A
authors.lastname: Yuno
authors.forename: Hirotake
authors.initials: H
authors.lastname: Tsukamoto
authors.forename: Satoru
authors.initials: S
authors.lastname: Senju
authors.forename: Sachiko
authors.initials: S
authors.lastname: Yoshimura
authors.forename: Ryuji
authors.initials: R
authors.lastname: Osawa
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Kuroda
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Hirayama
authors.forename: Atsushi
authors.initials: A
authors.lastname: Irie
authors.forename: Akinobu
authors.initials: A
authors.lastname: Hamada
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Jono
authors.forename: Koji
authors.initials: K
authors.lastname: Yoshida
authors.forename: Takuya
authors.initials: T
authors.lastname: Tsunoda
authors.forename: Hirotsugu
authors.initials: H
authors.lastname: Kohrogi
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Yoshitake
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Masanori
authors.initials: M
authors.lastname: Shinohara
authors.forename: Yasuharu
authors.initials: Y
authors.lastname: Nishimura
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D016022:Case-Control Studies; D018797:Cell Cycle Proteins / Q000276:immunology* / Q000378:metabolism; D002478:Cells, Cultured; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D005347:Fibroblasts / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D005434:Flow Cytometry; D006680:HLA Antigens / Q000276:immunology / Q000378:metabolism; D006258:Head and Neck Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051379:Mice; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D010446:Peptide Fragments / Q000276:immunology* / Q000378:metabolism; D040201:Platelet Membrane Glycoprotein IIb / Q000276:immunology* / Q000378:metabolism; D011994:Recombinant Proteins / Q000276:immunology / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology
chemical_list: D018797:Cell Cycle Proteins; D006680:HLA Antigens; C490197:NUF2 protein, human; D010446:Peptide Fragments; D040201:Platelet Membrane Glycoprotein IIb; D011994:Recombinant Proteins