title: An oncofetal antigen, IMP-3-derived long peptides induce immune responses of both helper T cells and CTLs.
abstract: Insulin-like growth factor II mRNA-binding protein 3 (IMP-3), an oncofetal antigen identified using genome-wide cDNA microarray analyses, is overexpressed in several malignancies. IMP-3-derived cytotoxic T lymphocyte (CTL) epitopes have been used for peptide-based immunotherapies against various cancers. In addition to CTLs, induction of tumor-associated antigen (TAA)-specific helper T (Th) cells is crucial for establishment of effective antitumor immunity. In this study, we aimed to identify IMP-3-derived long peptides (IMP-3-LPs) carrying CTL and promiscuous Th-cell epitopes for use in cancer immunotherapy. IMP-3-derived Th-cell epitopes that bind to multiple HLA-class II molecules were predicted by in silico analysis, and their immunogenicity was determined by utilizing human T cells. We identified two highly immunogenic IMP-3-LPs presented by multiple HLA-class II molecules. One of the IMP-3-LPs encompassed two CTL epitopes that have been used for peptide-vaccine immunotherapy in ongoing clinical trials. IMP-3-LPs-specific Th cells responded to autologous dendritic cells (DCs) loaded with the recombinant IMP-3 proteins, suggesting that these s (LPs) can be naturally processed and presented. The IMP-3-LPs and specific Th cells augmented the expansion of IMP-3-specific CTLs, which was further enhanced by programmed cell death-1 (PD-1) blockade. In addition, IMP-3-LP encapsulated in liposomes was efficiently cross-presented in vitro, and this LP successfully cross-primed CTLs in HLA-A2 transgenic mice (Tgm) in vivo. Furthermore, one of the IMP-3-LPs induced IMP-3-specific Th cells from peripheral blood mononuclear cells (PBMCs) of head-and-neck malignant tumor (HNMT) patients. These findings suggest the potential usefulness of IMP-3-LPs in propagating both Th cells and CTLs and may have implications for IMP-3-LPs-based cancer immunotherapy.
authors.affiliation: Department of Immunogenetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan; Department of Oral and Maxillofacial Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Hirayama
authors.affiliation: Department of Immunogenetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan; Department of Respiratory Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Tomita
authors.affiliation: Department of Immunogenetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan; Department of Oral and Maxillofacial Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Yuno
authors.affiliation: Department of Immunogenetics, Graduate School of Medical Sciences, Kumamoto University , Kumamoto, Japan.
authors.forename: Hirotake
authors.initials: H
authors.lastname: Tsukamoto
authors.affiliation: Department of Immunogenetics, Graduate School of Medical Sciences, Kumamoto University , Kumamoto, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Senju
authors.affiliation: Department of Immunogenetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan; Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Yuya
authors.initials: Y
authors.lastname: Imamura
authors.affiliation: Department of Immunogenetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan; Department of Biotechnology and Genetic Engineering, Mawlana Bhashani Science and Technology University, Tangail, Bangladesh.
authors.forename: Mohammad Abu
authors.initials: MA
authors.lastname: Sayem
authors.affiliation: Department of Immunogenetics, Graduate School of Medical Sciences, Kumamoto University , Kumamoto, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Irie
authors.affiliation: Department of Oral and Maxillofacial Surgery, Graduate School of Medical Sciences, Kumamoto University , Kumamoto, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Yoshitake
authors.affiliation: Department of Oral and Maxillofacial Surgery, Graduate School of Medical Sciences, Kumamoto University , Kumamoto, Japan.
authors.forename: Daiki
authors.initials: D
authors.lastname: Fukuma
authors.affiliation: Department of Oral and Maxillofacial Surgery, Graduate School of Medical Sciences, Kumamoto University , Kumamoto, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Shinohara
authors.affiliation: Department of Pharmacy, Kumamoto University Hospital, Kumamoto, Japan; Department of Clinical Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Akinobu
authors.initials: A
authors.lastname: Hamada
authors.affiliation: Department of Pharmacy, Kumamoto University Hospital, Kumamoto, Japan; Department of Clinical Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Jono
authors.affiliation: Department of Applied Chemistry, Graduate School of Engineering, Osaka Prefecture University , Sakai, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Yuba
authors.affiliation: Department of Applied Chemistry, Graduate School of Engineering, Osaka Prefecture University , Sakai, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Kono
authors.affiliation: OncoTherapy Science Incorporation, Research and Development Division, Kawasaki, Japan; Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, the University of Tokyo, Tokyo, Japan; AstraZeneca K.K., Oncology, Medical, Tokyo, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Yoshida
authors.affiliation: OncoTherapy Science Incorporation, Research and Development Division, Kawasaki, Japan; Merck-Living Innovation, Tokyo, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Tsunoda
authors.affiliation: Department of Oral and Maxillofacial Surgery, Graduate School of Medical Sciences, Kumamoto University , Kumamoto, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Nakayama
authors.affiliation: Department of Immunogenetics, Graduate School of Medical Sciences, Kumamoto University , Kumamoto, Japan.
authors.forename: Yasuharu
authors.initials: Y
authors.lastname: Nishimura
keywords: CD4+ T cell; Cancer immunotherapy; IMP-3; Th-cell epitope; head-and-neck malignant tumor