Abstract 1253: Improvement of the potency of the dendritic cell-based vaccine immunotherapy through local inhibition of TGF-β in tumor-draining lymph nodes.

Abstract

Abstract The dendritic cell (DC) -based vaccine immunotherapy has been a promising anti-cancer immunotherapy, but has been unable to elicit anti-tumor immune responses enough to eradicate the tumor in patients with advanced cancer. In order to develop the potent DC-based vaccine immunotherapy, it should be required to focus on the unique environment implicated in the induction of anti-tumor immune responses. Transforming growth factor-β (TGF-β), an immunosuppressive cytokine, is produced in the tumor microenvironment, and flows into tumor-draining lymph nodes (TDLs), primary priming sites for generation of anti-tumor immune responses. In TDLs, TGF-β plays a critical role in suppressing the induction of anti-tumor immune responses. In this study, we focused on TGF-β-mediated immunosuppression in TDLs, and examined whether local inhibition of TGF-β in TDLs could improve the potency of the DC-based vaccine immunotherapy in tumor-bearing mouse model. C57BL/6 mice bearing Lewis lung carcinoma (LLC1) subcutaneously were vaccinated with DCs loading LLC1-derived antigen. In order to inhibit TGF-β in TDLs, those mice were administered the plasmid DNA encoding the extracellular domain of TGF-β type II receptor fused to the human IgG heavy chain(TGFR DNA) near the established tumor intramuscularly. Soluble TGF-β type II receptor secreted from TGFR DNA-transfected cells is expected to function to attenuate TGF-β level in TDLs. After this combination therapy, anti-tumor immune responses elicited in those mice were evaluated. As results, the level of TGF-β in TDLs was decreased by administrations of TGFR DNA near the established tumor. The attenuation of TGF-β level in TDLs by TGFR DNA was able to suppress the proliferative activity of Foxp3+ regulatory T cells in TDLs. Regarding the induction of effector cells in TDLs, tumor antigen-specific CD8+ cells producing interferon-gamma were significantly increased by this combination therapy. Next, we evaluated the association between the local inhibition of TGF-β in TDLs and systemic anti-tumor immune responses. Tumor antigen-specific cytotoxic responses as well as natural killer activities were significantly enhanced through the local inhibition of TGF-β in TDLs, leading to effective suppression of tumor growth. Such potent anti-tumor immune responses were not achieved in mice that had been administered DC-based vaccine alone. Improvement of the induction of anti-tumor immune responses in TDLs by the local inhibition of TGF-β contributed to enhancement of systemic anti-tumor immune responses. In conclusion, inhibition of TGF-β-mediated immunosuppression in TDLs can enhance the potency of DC-based vaccine immunotherapy. This animal model provides for a novel rationale with DC-based vaccine immunotherapy. Citation Format: Koji Teramoto, Yasuhiko Ohshio, Takuya Fujita, Jun Hanaoka, Yataro Daigo. Improvement of the potency of the dendritic cell-based vaccine immunotherapy through local inhibition of TGF-β in tumor-draining lymph nodes. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1253. doi:10.1158/1538-7445.AM2013-1253