title: Vaccination with dendritic cells transfected with BAK and BAX siRNA enhances antigen-specific immune responses by prolonging dendritic cell life.
abstract: Dendritic cell-based vaccines have become an important approach for the treatment of malignancies. Numerous techniques have recently been designed to optimize dendritic cell activation, tumor antigen delivery to dendritic cells, and induction of tumor-specific immune responses in vivo. Dendritic cells (DCs), however, have a limited life span because they are subject to apoptotic cell death mediated by T cells, hindering their long-term ability to prime antigen-specific T cells. Small interfering RNA targeting Bak and Bax antiapoptotic proteins can be used to allow transfected DCs to resist killing by T cells in vivo. In this study, we show that human papillomavirus E7-loaded dendritic cells transfected with BAK/BAX siRNA downregulate Bak and Bax protein expression and become resistant to killing by T cells, leading to enhanced E7-specific CD8+ T cell activation and antitumor effects in vivo. More importantly, we found that vaccination with E7-loaded DCs transfected with BAK/BAX siRNA was capable of generating a strong therapeutic effect in vaccinated mice, compared with DCs transfected with control siRNA. Our data indicate that transfection of dendritic cells with BAK/BAX siRNA represents a plausible strategy for enhancing dendritic cell-based vaccine potency.
authors.affiliation: Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland 21205, USA.
authors.forename: Shiwen
authors.initials: S
authors.lastname: Peng
authors.forename: Tae Woo
authors.initials: TW
authors.lastname: Kim
authors.forename: Jin Hyup
authors.initials: JH
authors.lastname: Lee
authors.forename: Mu
authors.initials: M
authors.lastname: Yang
authors.forename: Liangmei
authors.initials: L
authors.lastname: He
authors.forename: Chien-Fu
authors.initials: CF
authors.lastname: Hung
authors.forename: T-C
authors.initials: TC
authors.lastname: Wu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000276:immunology*; D015536:Down-Regulation; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D008213:Lymphocyte Activation; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009856:Oncogene Proteins, Viral / Q000737:chemistry / Q000276:immunology; D050725:Papillomavirus E7 Proteins; D010455:Peptides / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000276:immunology*; D034741:RNA, Small Interfering / Q000378:metabolism*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014162:Transfection; D014611:Vaccination; D014765:Viral Vaccines / Q000276:immunology; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein
chemical_list: C494772:BAK1 protein, human; C494826:BAX protein, human; C494773:Bak1 protein, mouse; C494827:Bax protein, mouse; D008565:Membrane Proteins; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D010455:Peptides; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D014765:Viral Vaccines; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; C059731:oncogene protein E7, Human papillomavirus type 16