TGF-beta insensitive dendritic cells: an efficient vaccine for murine prostate cancer
ABSTRACT
Dendritic cells (DCs) are highly potent initiators of the immune response, but DC effector functions are often inhibited by immunosuppressants such as transforming growth factor beta (TGF-beta). The present study was conducted to develop a treatment strategy for prostate cancer using a TGF-beta-insensitive DC vaccine. Tumor lysate-pulsed DCs were rendered TGF-beta insensitive by dominant-negative TGF-beta type II receptor (TbetaRIIDN), leading to the blockade of TGF-beta signals to members of the Smad family, which are the principal cytoplasmic intermediates involved in the transduction of signals from TGF-beta receptors to the nucleus. Expression of TbetaRIIDN did not affect the phenotype of transduced DCs. Phosphorylated Smad-2 was undetectable and expression of surface co-stimulatory molecules (CD80/CD86) were upregulated in TbetaRIIDN DCs after antigen and TGF-beta1 stimulation. Vaccination of C57BL/6 tumor-bearing mice with the TbetaRIIDN DC vaccine induced potent tumor-specific cytotoxic T lymphocyte responses against TRAMP-C2 tumors, increased serum IFN-gamma and IL-12 level, inhibited tumor growth and increased mouse survival. Furthermore, complete tumor regression occurred in two vaccinated mice. These results demonstrate that blocking TGF-beta signals in DC enhances the efficacy of DC-based vaccines.