Regulation of dendritic cell function and tumor immunity by TIM-3 Tumor immunity is predicated upon the de novo activation and expansion of antigen-specific cytotoxic T lymphocytes. However, to impact tumor growth these T cells must also infiltrate into tumors, overcome a suppressive environment, and avoid becoming exhausted in the presence of persistent antigen, barriers that are thought to be major impediments to immunotherapy. Conventional dendritic cells are well established as the central inducers of the adaptive immune response, but emerging evidence suggests they may also play in supporting T cell activity within peripheral tissues, including tumors. In support of this, we have found that TIM- 3 (T-cell immunoglobulin and mucin domain containing-3) is highly expressed by tumor dendritic cells, and that TIM-3 blockade induces expression of the chemokine CXCL9 in vitro and in vivo, thereby promoting T cell cytotoxic effector function in models of mammary carcinoma. Here we propose to identify the dendritic cell activation pathways altered by TIM-3, determine if non-migratory dendritic cells maintain T cell function within tumors, and determine the role of CXCL9 expression by dendritic cells in tumor immunity. These studies will delineate a putative dendritic cell regulatory pathway and improve our understanding of the role of dendritic cells within tumors, both factors that may have important implications for the design of combinatorial immunotherapies.
Regulation of dendritic cell function and tumor immunity by TIM-3 Dendritic cells are necessary for induction of an anti-tumor immune response, but the process by which tumor dendritic cells are activated to promote T cell responses is poorly characterized. In preliminary results we have identified that expression of the molecule TIM-3 on dendritic cells suppresses their ability to produce chemokines, suggesting a potential immune regulatory axis within tumors. Here we will determine how TIM-3 suppresses activation of dendritic cells and utilize this system to further our understanding of how dendritic cells modulate the tumor immune microenvironment, with the goal of optimizing strategies for combinatorial immunotherapy.
