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: Yusuke Tomita, Akira Yuno, Hirotake Tsukamoto, Satoru Senju, Sachiko Yoshimura, Ryuji Osawa, Yasuhiro Kuroda, Masatoshi Hirayama, Atsushi Irie, Akinobu Hamada, Hirofumi Jono, Koji Yoshida, Takuya Tsunoda, Hirotsugu Kohrogi, Yoshihiro Yoshitake, Yusuke Nakamura, Masanori Shinohara, Yasuharu Nishimura
• Journal: International journal of cancer (Int J Cancer) Vol. 134 Issue 2 Pg. 352-66 (Jan 15 2014) ISSN: 1097-0215 [Electronic] United States
• PMID: 24734272 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cell Cycle Proteins
• HLA Antigens
• NUF2 protein, human
• Peptide Fragments
• Platelet Membrane Glycoprotein IIb
• Recombinant Proteins

Topics

• Animals
• CD4-Positive T-Lymphocytes (immunology, metabolism, pathology)
• CD8-Positive T-Lymphocytes (immunology, metabolism, pathology)
• Case-Control Studies
• Cell Cycle Proteins (immunology, metabolism)
• Cells, Cultured
• Clinical Trials, Phase I as Topic
• Clinical Trials, Phase II as Topic
• Fibroblasts (immunology, metabolism, pathology)
• Flow Cytometry
• HLA Antigens (immunology, metabolism)
• Head and Neck Neoplasms (immunology, metabolism, pathology)
• Humans
• Mice
• Neoplasm Metastasis
• Neoplasm Recurrence, Local (immunology, metabolism, pathology)
• Peptide Fragments (immunology, metabolism)
• Platelet Membrane Glycoprotein IIb (immunology, metabolism)
• Recombinant Proteins (immunology, metabolism)
• Th1 Cells (immunology, metabolism, pathology)