Targeting the Epigenome to Improve Responses to Immunotherapy

项目摘要 常规的树突状细胞（cDC）是适应性免疫应答的中心调节因子，并且已经被广泛应用。 显示为诱导T细胞介导的抗肿瘤免疫所需。特别是，cDC的一个子集 cDC 1负责将肿瘤抗原转运至淋巴结并交叉呈递抗原， 以激活细胞毒性T淋巴细胞，从而诱导抗肿瘤应答。我们最近观察到， 3（含T细胞免疫球蛋白和粘蛋白结构域-3）在人和鼠乳腺癌中cDC上的表达 并发现TIM-3阻断剂改善了对标准护理紫杉醇化疗的反应， 三阴性和管腔型B疾病的模型。这是通过增加趋化因子表达而发生的， cDCs，没有相应的T细胞浸润，这使我假设， 肿瘤内的cDC和T细胞是成功免疫治疗的关键决定因素。在F99部分， 因此，本申请将寻求确定TIM-3阻断是否改变T细胞的空间组织， 如果这是治疗效果的原因。在本提案的K 00阶段，我将扩大这些研究， 评估cDC/T细胞聚集是否是对免疫检查点阻断和其他免疫应答的先决条件。 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.