Regulation of dendritic cell function and tumor immunity by TIM-3

项目总结 TIM-3对树突状细胞功能和肿瘤免疫的调节作用 肿瘤免疫依赖于抗原特异性细胞毒T细胞的从头激活和扩增 淋巴细胞。然而，为了影响肿瘤生长，这些T细胞也必须渗透到肿瘤中，克服 抑制环境，避免在存在持久性抗原的情况下筋疲力尽，这些障碍 被认为是免疫治疗的主要障碍。传统的树突状细胞被很好地建立为 适应性免疫反应的中心诱导者，但新出现的证据表明，它们也可能起到作用 支持包括肿瘤在内的周围组织中的T细胞活动。为了支持这一点，我们发现蒂姆- 3(T细胞免疫球蛋白和粘蛋白结构域包含-3)由肿瘤树突状细胞高表达，并且 TIM-3阻断体内外诱导趋化因子CXCL9的表达，从而促进T细胞 细胞毒效应在乳腺癌模型中的作用。在这里，我们建议鉴定树突状细胞 TIM-3改变的激活通路决定非迁移性树突状细胞是否维持T细胞功能 并确定树突状细胞表达CXCL9在肿瘤免疫中的作用。这些研究将 描绘一条可能的树突状细胞调控途径，提高我们对树突状细胞的作用的理解 肿瘤内的细胞，这两个因素可能对组合方案的设计具有重要意义 免疫疗法。

PROJECT SUMMARY 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.