Tumour necrosis factor-α (TNF-α) 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-α

Authors


and present address: Dr Jim Xiang, Saskatoon Cancer Center, 20 Campus Drive, Saskatoon, Saskatchewan, Canada, S7N 4H4. E-mail: JXiang@SCF.SK.CA

Summary

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-α (TNF-α) 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-α. 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-α transgene. Our data shows that transfection of DCs with recombinant adenovirus AdV-TNF-α resulted in greater maturation of the DCs than occurred with control DCs cultured in exogenous TNF-α, as determined by up-regulated expression of pro-inflammatory cytokines (e.g. interleukins 1β and 18), chemokines [e.g. interferon-γ-inducible protein-10 and macrophage inflammatory protein-1β (MIP-1β)], 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-3βin 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-α-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-α-cultivated DCs. Thus, DCs engineered to secrete TNF-α may offer a new strategy in DC cancer vaccines.

Ancillary