Determining the role of dendritic cells and spatial localization in anti-tumor immunity

项目摘要 传统的树突状细胞(CDCs)是获得性免疫反应的中央调节细胞，并已 被证明是诱导T细胞介导的抗肿瘤免疫所必需的。特别是，CDC的一个子集 (Cdc1)负责将肿瘤抗原运送到淋巴结，并按顺序递送抗原。 激活细胞毒性T淋巴细胞，从而诱导抗肿瘤反应。我们最近观察到蒂姆- 3(T细胞免疫球蛋白和粘蛋白结构域含-3)在人和小鼠乳腺CDC上的表达 肿瘤，并发现TIM-3阻断改善了对标准护理紫杉醇化疗的反应 三阴性和腔性B病模型。这是通过增加趋化因子的表达来实现的 CDC，没有相应的In T细胞渗透，这让我假设 肿瘤内的CDC和T细胞是免疫治疗成功的关键决定因素。在的F99部分 因此，这项应用I将寻求确定TIM-3封锁是否改变了T细胞的空间组织，以及 如果这是治疗效果的责任。在本提案的K00阶段，我将把这些研究扩展到 评估CDC/T细胞聚集是否是免疫检查点阻断和其他反应的先决条件 治疗方式。

Project Summary Conventional dendritic cells (cDCs) are central regulators of the adaptive immune response, and have been shown to be required for the induction of T cell-mediated anti-tumor immunity. In particular, a subset of cDCs (cDC1) is responsible for transporting tumor antigens to the lymph node and cross presenting antigen in order to activate cytotoxic T lymphocytes, thereby inducing an anti-tumor response. We have recently observed TIM- 3 (T-cell immunoglobulin and mucin domain containing-3) expression on cDCs in human and murine mammary tumors, and found that TIM-3 blockade improved response to standard-of-care paclitaxel chemotherapy in models of triple-negative and luminal B disease. This occurred through increased chemokine expression by cDCs, without a corresponding in T cell infiltration, leading me to hypothesize that the spatial localization of cDCs and T cells within tumors is a critical determinant of successfully immunotherapy. In the F99 portion of this application I will therefore seek to determine if TIM-3 blockade alters the spatial organization of T cells, and if this is responsible for therapeutic efficacy. In the K00 phase of this proposal I will expand these studies to evaluate whether cDC/T cell clustering is a prerequisite for response to immune checkpoint blockade and other therapeutic modalities.