title: Tumour necrosis factor-alpha (TNF-alpha) transgene-expressing dendritic cells (DCs) undergo augmented cellular maturation and induce more robust T-cell activation and anti-tumour immunity than DCs generated in recombinant TNF-alpha.
abstract: Tumour antigen presentation by dendritic cells (DCs) to T cells in lymphoid organs is crucial for induction of anti-tumour immune responses. It has been previously reported that tumour necrosis factor-alpha (TNF-alpha) is required for DC activation and subsequent induction of optimal immune responses, and thus DCs for anti-tumour vaccination are often generated by culture in exogenous TNF-alpha. In the present study, we investigated the effect on anti-tumour immunity of vaccination with Mut1 tumour peptide-pulsed DCs engineered to express a TNF-alpha transgene. Our data shows that transfection of DCs with recombinant adenovirus AdV-TNF-alpha resulted in greater maturation of the DCs than occurred with control DCs cultured in exogenous TNF-alpha, as determined by up-regulated expression of pro-inflammatory cytokines (e.g. interleukins 1beta and 18), chemokines [e.g. interferon-gamma-inducible protein-10 and macrophage inflammatory protein-1beta (MIP-1beta)], the CC chemokine receptor CCR7, and immunologically important cell surface molecules (CD40, CD86 and intercellular adhesion molecule-1). These transgenic DCs stimulated stronger allogeneic T-cell responses in vitro and T-cell activation in vivo; displayed 2.4-fold enhanced chemotactic responses to the MIP-3betain vitro (P<0.05); and, perhaps most importantly, trafficked into the draining lymph nodes dramatically (seven-fold, P<0.01) more efficiently than the control DCs. Our data also demonstrate that vaccination of mice with Mut1 peptide-pulsed, AdV-TNF-alpha-transfected DCs stimulated more efficient in vitro Mut1-specific CD8+ cytotoxic T-cell responses and solid tumour immunity in vivo, when compared to the in vitro TNF-alpha-cultivated DCs. Thus, DCs engineered to secrete TNF-alpha may offer a new strategy in DC cancer vaccines.
authors.affiliation: Department of Oncology, Research Unit, Saskatchewan Cancer Agency, University of Saskatchewan, Saskatoon, Saskatchewan, Canada S7N 0W0.
authors.forename: Weidong
authors.initials: W
authors.lastname: Zhang
authors.forename: Zhuang
authors.initials: Z
authors.lastname: Chen
authors.forename: Fang
authors.initials: F
authors.lastname: Li
authors.forename: Huse
authors.initials: H
authors.lastname: Kamencic
authors.forename: Bernie
authors.initials: B
authors.lastname: Juurlink
authors.forename: John R
authors.initials: JR
authors.lastname: Gordon
authors.forename: Jim
authors.initials: J
authors.lastname: Xiang
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D019496:Cancer Vaccines / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology; D002633:Chemotaxis / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology*; D005822:Genetic Vectors; D007111:Immunity, Cellular; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000276:immunology* / Q000517:prevention & control; D011994:Recombinant Proteins / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D014162:Transfection; D019076:Transgenes; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology*
chemical_list: D019496:Cancer Vaccines; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha