Journal
CANCER IMMUNOLOGY IMMUNOTHERAPY
Volume 56, Issue 11, Pages 1785-1793Publisher
SPRINGER
DOI: 10.1007/s00262-007-0322-3
Keywords
dendritic cell; immuno-gene therapy; prostate cancer; receptor; TGF-beta; vaccination
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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 (T beta RIIDN), 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 T beta RIIDN 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 T beta RIIDN DCs after antigen and TGF-beta 1 stimulation. Vaccination of C57BL/6 tumor-bearing mice with the T beta RIIDN 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.
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