Activation of Plasmacytoid Dendritic Cells (pDCs) to Induce Antitumor Activity

性状（由申请方提供）：虽然对病毒病原体的免疫应答较强，但抗肿瘤免疫力较弱。这主要是由于病毒成分通过Toll样受体（TLR）激活先天免疫细胞的能力。然而，来源于宿主组织的肿瘤不能激活强烈的先天免疫应答。浆细胞样树突状细胞（pDC）是针对病毒的有效先天免疫应答的核心，并直接导致其他免疫细胞的激活，包括骨髓树突状细胞和自然杀伤细胞，然后导致有效的适应性T细胞免疫应答。先天性免疫应答不仅在触发强T细胞引发方面很重要，而且在病原体部位诱导炎症方面也很重要，这导致引发的T细胞迁移到感染部位。我们的目标是利用这些原理来产生强大的抗肿瘤免疫应答。总体假设是，使用TLR激动剂活化浆细胞样树突状细胞将导致炎症级联反应，其将导致改善的T细胞引发以及增强的向肿瘤部位的迁移和在肿瘤部位的功能。提出了四个综合项目和三个核心，以评估浆细胞样树突状细胞在抗肿瘤免疫中的作用，并确定改进疫苗策略的方法。这些项目代表了从实验室到临床终点对这一问题的系统评价。这包括浆细胞样树突状细胞相互作用的机制评估，pDC在鼠和人模型系统中的研究，利用TLR激动剂在体内激活pDC的临床疫苗试验，以及这些研究的整合。项目1将集中于评估人pDC、自然杀伤（NK）细胞和B淋巴细胞之间在存在和不存在TLR激动剂活化的情况下的分子相互作用。在项目2中，将在鼠肿瘤模型中进行pDC相互作用的进一步表征。在项目3中，我们将检查人肿瘤样品中的内源性pDC。我们的初步证据表明，由于缺乏激活刺激，肿瘤部位的pDC没有功能。在项目4中，我们将尝试通过在疫苗部位施用TLR激动剂来在患者中提供这些pDC活化信号，以诱导肿瘤特异性T细胞的活化和增殖，以及全身诱导转移性病变中的炎症，以增强T细胞向肿瘤部位的迁移和在肿瘤部位的功能。行政核心、生物统计和数据管理核心以及免疫监测核心提供的资源对这一努力至关重要，并将为样本的无缝整合和评估以及数据分析提供资源和结构。本申请的目标是将从成功的抗病毒免疫反应分析中收集的基本原则应用于改善抗肿瘤免疫反应的发展，这些研究可能会产生可适用于其他癌症的发现。

DESCRIPTION (provided by applicant): While the immune response against viral pathogens is strong, antitumor immunity is weak. This is largely due to the ability of viral elements to activate innate immune cells through toll like receptors (TLRs). However, tumors, which are derived from host tissues, are incapable of activating a strong innate immune response. Plasmacytoid dendritic cells (pDCs) are central to the potent innate immune response against viruses and lead directly to the activation of other immune cells, including myeloid dendritic cells and natural killer cells which then lead to a potent adaptive T-cell immune response. The innate immune response is important in not only triggering strong T-cell priming, but also in inducing inflammation at the site of pathogen which leads to migration of primed T-cells to the infected site. It is our goal to utilize these principles to generate a strong antitumor immune response. The overall hypothesis is that activation of plasmacytoid dendritic cells using TLR agonists will result in an inflammatory cascade that will lead to both improved T-cell priming as well as enhanced migration to and function at the tumor site. Four integrated projects and three cores are proposed to evaluate the role of plasmacytoid dendritic cells in antitumor immunity and identify methods to improve vaccine strategies. These projects represent a systematic evaluation of this issue from laboratory to clinical endpoints. This includes a mechanistic evaluation of plasmacytoid dendritic cell interactions, studies of pDCs in murine and human model systems, a clinical vaccine trial utilizing TLR agonists to activate pDCs in vivo, and the integration of these studies. Project 1 will focus on evaluating the molecular interactions between human pDCs, natural killer (NK) cells, and B lymphocytes, in the presence and absence of activation by TLR agonists. In Project 2, further characterization of pDC interactions will be performed in a murine tumor model. In Project 3, we will examine endogenous pDC in human tumor samples. Our preliminary evidence suggests that pDC in the tumor site are not functional due to lack of activation stimuli. In Project 4, we will attempt to provide these pDC activation signals in patients by the administration of TLR agonists at the vaccine site to induce the activation and proliferation of tumor-specific T-cells as well as systemically to induce inflammation in metastatic lesions in order to enhance T-cell migration to and function at the tumor site. The resources provided by the Administrative Core, the Biostatistical and Data Management Core, and the Immune Monitoring Core are crucial to this effort, and will provide the resources and structure for the seamless integration and evaluation of samples and analyses of data. The goal of this application is to apply the basic principles gleaned from analysis of successful antiviral immune responses to the development of improved antitumor immune responses, and these studies may produce findings that can be applicable to other cancers.