title: Polyarginine-mediated protein delivery to dendritic cells presents antigen more efficiently onto MHC class I and class II and elicits superior antitumor immunity.
abstract: Protein transduction domains (PTDs) have been used increasingly to deliver reagents to a variety of cell types in vitro and in vivo. We have previously shown that HIV TAT-PTD-containing whole protein antigens (Ags)-transduced dendritic cells (DCs) stimulated Ag-specific CD8+ and CD4+ T cells. Although the cytotoxic T lymphocytes (CTL) activity generated was sufficient to prevent engraftment of mice with Ag-expressing tumors, treatment of tumor-bearing mice with TAT-PTD Ag-transduced DCs resulted in tumor regression in some animals. Recently, several other PTDs were reported to promote higher transduction efficiencies than TAT-PTD. To evaluate the role of individual PTDs in induction of immune responses in tumor vaccination studies, we engineered recombinant fusion Ovalbumin (OVA) that contained three differrent PTDs, including the most efficacious known PTD (polyarginine (R9)-PTD). Our results demonstrated that R9-PTD-containing OVA transduced DCs most efficiently, and that transduction efficacy was closely correlated with the extent of Ag-specific CD4+ and CD8+ T-cell activation in vitro and in vivo. Repeated vaccination with R9-PTD-OVA-transduced DC in (OVA-expressing) tumor-bearing mice induced enhanced antitumor immunity, and elicited complete rejection of tumors when DC was co-injected with adjuvants. This vaccination strategy may be clinically applicable, and offers theoretical and practical advantages to those that are in current use.
authors.affiliation: Department of Dermatology, University of Yamanashi, School of Medicine, Chuo-shi, Yamanashi, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Mitsui
authors.forename: Takashi
authors.initials: T
authors.lastname: Inozume
authors.forename: Reiko
authors.initials: R
authors.lastname: Kitamura
authors.forename: Naotaka
authors.initials: N
authors.lastname: Shibagaki
authors.forename: Shinji
authors.initials: S
authors.lastname: Shimada
mesh_terms: D000276:Adjuvants, Immunologic / Q000493:pharmacokinetics; D000818:Animals; D017951:Antigen Presentation / Q000276:immunology*; D000970:Antineoplastic Agents / Q000276:immunology / Q000493:pharmacokinetics; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology / Q000493:pharmacokinetics*; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D000939:Epitopes / Q000276:immunology; D005260:Female; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000276:immunology / Q000628:therapy*; D010047:Ovalbumin / Q000276:immunology / Q000493:pharmacokinetics; D010455:Peptides / Q000493:pharmacokinetics*; D010844:Picibanil / Q000276:immunology / Q000493:pharmacokinetics; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D000970:Antineoplastic Agents; D019496:Cancer Vaccines; D000939:Epitopes; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; D010455:Peptides; C015462:polyarginine; D010844:Picibanil; D010047:Ovalbumin