The effect of transforming growth factor-beta on dendritic cell-based cancer vaccines

Abstract

The ability of dendritic cells (DCs) to stimulate tumor-specific T lymphocyte responses has made them prime candidates for cancer immunotherapy. Numerous studies have focused on enhancing the ability of DCs to stimulate the immune response. Commonly overlooked is the immunosuppressive milieu of the tumor microenvironment. Many tumor types including the murine mammary carcinoma cell line 4T1, produce large quantities of the immunosuppressive cytokine transforming growth factor-beta (TGF-β). These studies have determined that TGF-β suppresses numerous dendritic cell functions involved in generating an effective anti-tumor immune response. By reducing the amount of TGF-β present in the tumor-bearing host the migratory ability and anti-tumor activity of DCs are enhanced. Adenovirus-mediated Smad7 gene transfer, was able to reduce the responsiveness of DCs to TGF-β in vitro. Vaccination of tumor-bearing mice with AdSmad7-infected DCs resulted in enhanced IFN-γ secretion by tumor draining lymph node (TDLN) cells. However, this did not translate to improved ant-tumor activity. These results stress the necessity to eliminate tumor-derived immunosuppressive molecules such as TGF-β in order to improve the effectiveness of DC-based vaccines in treating cancer.