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

Abstract

Previous fundamental or clinical trials of dendritic cell (DC) vaccine against pancreatic ductal adenocarcinoma (PDAC) revealed the burgeoning neoadjuvant immunotherapy. Microarray studies indicated that multiple ingredients of the transfer growth factor beta (TGF-β) pathway were overexpressed 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 hypothesis that combining DC vaccine with TGF-β 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-β 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)-γ, 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-β antibody or TGF-β cytokine, respectively, in the co-culture system, we found IFN-γ producing was extremely higher and T cell apoptosis relatively descent with TGF-β blockage (p < 0.05). The murine PDAC model demonstrated a survival advantage treated with anti-TGF-β antibody combined with DC vaccine when compared with monotherapy controls (p < 0.05). Therefore, these findings indicated that, through neutralizing TGF-β associated with DC vaccine, the anti-tumor immunity is highly elevated and this combinational therapy will provide an efficacious prospect.