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

激活浆细胞样树突状细胞 (pDC) 诱导抗肿瘤活性

• 批准号: 8135425
• 负责人: PATRICK HWU
• 金额: $ 201.73万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-10 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8135425
• 关键词: Activation; Plasmacytoid; Dendritic; Cells; pDCs

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.

描述（由申请人提供）：虽然针对病毒病原体的免疫反应很强，但抗肿瘤免疫力很弱。这主要是由于病毒元件能够通过 Toll 样受体 (TLR) 激活先天免疫细胞。然而，源自宿主组织的肿瘤无法激活强大的先天免疫反应。浆细胞样树突细胞 (pDC) 是针对病毒的有效先天免疫反应的核心，并直接导致其他免疫细胞的激活，包括骨髓树突细胞和自然杀伤细胞，然后导致有效的适应性 T 细胞免疫反应。先天免疫反应不仅能触发强烈的 T 细胞启动，而且还能在病原体部位诱发炎症，从而导致启动的 T 细胞迁移至感染部位。我们的目标是利用这些原理产生强大的抗肿瘤免疫反应。总体假设是，使用 TLR 激动剂激活浆细胞样树突状细胞将导致炎症级联反应，从而改善 T 细胞启动并增强向肿瘤部位的迁移和功能。提出了四个综合项目和三个核心来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。这些项目代表了对这个问题从实验室到临床终点的系统评估。这包括浆细胞样树突状细胞相互作用的机制评估、小鼠和人类模型系统中 pDC 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 将重点评估在存在或不存在 TLR 激动剂激活的情况下，人类 pDC、自然杀伤 (NK) 细胞和 B 淋巴细胞之间的分子相互作用。在项目 2 中，将在小鼠肿瘤模型中进一步表征 pDC 相互作用。在项目 3 中，我们将检查人类肿瘤样本中的内源性 pDC。我们的初步证据表明，肿瘤部位的 pDC 由于缺乏激活刺激而无法发挥功能。在项目4中，我们将尝试通过在疫苗部位施用TLR激动剂来向患者提供这些pDC激活信号，以诱导肿瘤特异性T细胞的激活和增殖，并系统性地诱导转移性病灶中的炎症，从而增强 T 细胞迁移至肿瘤部位并在肿瘤部位发挥作用。管理核心、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于这项工作至关重要，并将为样本的无缝集成和评估以及数据分析提供资源和结构。本申请的目标是将成功的抗病毒免疫反应分析中收集到的基本原理应用于改进抗肿瘤免疫反应的发展，并且这些研究可能会产生可适用于其他癌症的发现。