Abstract 3621: Regulation of antigen-presentaion by dendritic cells by TLR ligands and its application to cancer vaccine immunotherapy
Authors: Junya Ohtake, Takuto Kishikawa, Shun Kaneumi, Kazutaka Masuko, Yosuke Ono, Kentaro Sumida, Satoshi Terada, Toshiyuki Kita, Hidemitsu Kitamura
Journal: Cancer Research (2014)

Abstract Dendritic cells (DCs), one of the most powerful antigen presenting cells (APCs), are crucial not only for the innate immunity but also for the central role of the antigen-specific immune responses through activation of CD4+T and CD8+T cells. Generally, professional APCs such as DCs have a characteristic to initiate the strong T cell-immune responses because of the signals from costimulatory molecules and cytokines in addition to antigen-loaded MHCs compared with other APCs. Tumor antigen-pulsed DCs strongly prime both CD4+T and CD8+T cells capable of recognizing and killing tumor cells in response to the antigens on the target cells. Therefore, the effective antigen presentation by DCs is required for application of DC-mediated cancer immunotherapy. Numerous clinical studies using the HLA class I binding short peptides have been performed to activate tumor antigen-specific cytotoxic T cells (CTLs) in cancer patients. However, remarkable results such as the complete disappearance of tumors is still limited. Therefore, we focused on the function of DCs as professional APCs. In this study, we first prepared long peptides of tumor antigens including MHC class I and class II epitopes to uptake by DCs and to activate effector CTLs and Th cells, effectively. Next, we examined the effect of adjuvants or cytokines on DC function to activate tumor-antigen specific CTLs and Th cells, because it was thought that the maturation of DCs was an important factor for the induction of antigen specific T cells. We used OK-432, poly I:C, LPS, IFN-α, IFN-β, IFN-γ, IL-4, IL-6, and TGF-β in addition to GM-CSF for induction or stimulation with DCs. As a result, we observed that upregulation of MHC class I and class II expressions on DCs after stimulation with TLR ligands and cytokines except IL-6 and TGF-β. In this study, we found that IL-6 suppressed the function of DCs, whereas TGF-β inhibited the differentiation of DCs. Furthermore, we confirmed that IL-12 production by DCs after stimulation with OK-432 and poly I:C, but not LPS or other cytokines. Then, we examined the antigen-uptake and activation of antigen-specific CD4+T and CD8+T cells by using OK-432- or poly I:C-treated DCs. As a result, it became clear that we could induce antigen-specific Th cells and CTLs more effectively by using long peptides than short peptides. In addition, we confirmed that antigen-specific cytokine production by T cells was attenuated by the blockade of endocytosis and proteasome of DCs, suggesting the dynamics of antigen processing of the long peptides in DCs. We are now investigating for the novel regulator of DCs to generate antigen-specific T cells in cancer patients, which would promote the effect of the cancer vaccines. Citation Format: Junya Ohtake, Takuto Kishikawa, Shun Kaneumi, Kazutaka Masuko, Yosuke Ono, Kentaro Sumida, Satoshi Terada, Toshiyuki Kita, Hidemitsu Kitamura. Regulation of antigen-presentaion by dendritic cells by TLR ligands and its application to cancer vaccine immunotherapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3621. doi:10.1158/1538-7445.AM2014-3621