Neutralizing TGF-β promotes anti-tumor immunity of dendritic cells against pancreatic cancer by regulating T lymphocytes

Previous fundamental or clinical trials of dendritic cell (DC) vaccine against pancreatic ductal adeno-carcinoma (PDAC) revealed the burgeoning neoadjuvant immunotherapy. Microarray studies indicated that multiple ingredients of the transfer growth factor beta (TGF-beta) pathway were over-expressed in PDAC, which inhibited the intratumoral immune response. To explore whether the DC volume in tumor microenvironment contributes to the differentiation of T cell cohort and test the hypo-thesis that combining DC vaccine with TGF-beta inhibitors will elevate the anti-tumor immune response, we managed to co-culture T cells in vitro with pancreatic cancer cells and DCs in different concentrations, and combine TGF-beta blockage with DC vaccine therapy in a murine model of pancreatic cancer. In in vitro studies, we discovered that CD8(+) T cytotoxic cell (Tc) presented a significant advantage and lower volume of CD4(+) T helper cell (Th) existed with a certain elevated DC concentration (p < 0.05), associated with declined interleukin (IL)-10 and increased interferon (IFN)-gamma, which suggested with the DC volume increasing, the enhancing immune effect may represent a great advantage in such a system (p < 0.05). When interfered with anti-TGF-beta antibody or TGF-beta cytokine, respectively, in the co-culture system, we found IFN-gamma producing was extremely higher and T cell apoptosis relatively descent with TGF-beta blockage (p < 0.05). The murine PDAC model demonstrated a survival advantage treated with anti-TGF-beta antibody combined with DC vaccine when compared with monotherapy controls (p < 0.05). Therefore, these findings indicated that, through neutralizing TGF-beta associated with DC vaccine, the anti-tumor immunity is highly elevated and this combinational therapy will provide an efficacious prospect.