PDGF signaling in pediatric brain tumors

摘要 高级别胶质瘤（HGG）是最致命的儿童脑肿瘤之一。尽管我们尽了最大努力， 迄今为止已经改善了HGG儿童的存活率。所有这些儿童在确诊后1-2年内死亡。一 目前的抗肿瘤治疗不能提供持久反应的关键原因是 肿瘤微环境了解小儿HGG的免疫微环境对于 开发基于免疫疗法的试验，并预测对免疫疗法的反应，但不幸的是， 仍然是一个未满足的需求。本提案将提供设计所需的关键信息， 未来计划对这种疾病进行免疫试验。我们的初步数据显示， pHGG微环境中丰富的非肿瘤细胞是称为肿瘤相关的免疫细胞 巨噬细胞（TAM）。TAM浸润增加与pHGG-1细胞存活时间缩短相关。 产鼠该提案的主要目标是分析细胞组成，定位和 TAM的分子谱（骨髓来源的与常驻的小胶质细胞），以及表征 它们在pHGG中渗透的空间和时间动态。此外，该提案将使用遗传 以及靶向IL-1β/IL 1 R1信号通路的药理学方法，并确定其 对pHGG中肿瘤生长和TAM浸润影响。 表征肿瘤细胞-TAM关系是开发有效免疫疗法的先决条件， 利用免疫抑制性先天免疫的内在功能，使T细胞有效地 消除肿瘤细胞。

Abstract High-grade glioma (HGG) is one of the deadliest childhood brain tumors. Despite our best effort, no treatment to date has improved survival of children with HGG. All these children die within 1-2 years of diagnosis. One critical reason that current anti-neoplastic therapies fail to provide a durable response is the adaptive nature of the tumor microenvironment. Understanding the immune microenvironment of pediatric HGG is paramount to developing immunotherapy-based trials, and predicting response to immunotherapy, but unfortunately this remains an unmet need. This proposal will provide the critical lacking information required for the design of future planned immunotherapeutic trials for this disease. Our preliminary data demonstrate that the most abundant non-neoplastic cells in pHGG microenvironment are immune cells called are tumor-associated macrophages (TAMs). Increased infiltration of TAMs is associated with decreased survival time of pHGG- bearing mice. The major goals of this proposal are to analyze the cellular composition, localization and molecular profiles of TAMs (bone marrow-derived vs. resident microglia), as well as to characterize the spatial and temporal dynamics of their infiltration in pHGG. Additionally, this proposal will use genetic and pharmacological approaches to target the IL-1β/IL1R1 signaling pathways, and determine their impact on tumor growth and TAM infiltration in pHGG. Characterizing the tumor cell-TAM relationship is a prerequisite for developing effective immunotherapies that leverage the intrinsic functions of the immunosuppressive innate immunity to allow T cells to effectively eliminate tumor cells.