The role of Tumor associated macrophages in glioblastoma

肿瘤相关巨噬细胞在胶质母细胞瘤中的作用

• 批准号: 10132584
• 负责人: Dolores Hambardzumyan
• 金额: $ 45.86万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10132584
• 关键词: role; Tumor; associated; macrophages; glioblastoma

Project Summary (Abstract) Glioblastoma (GBM) is the most common and aggressive primary brain tumor. The infiltrative nature of tumor cells makes surgical resection incomplete. Furthermore, recurrence is inevitable despite radiation and temozolomide treatment and patients die within 15 months following diagnosis. GBM are divided into several molecular subtypes based on distinct gene expression profiles, including proneural (PN), mesenchymal (MES), classical (CL). One important reason that current anti-neoplastic therapies fail to provide a durable response in GBM is the adaptive nature of the tumor microenvironment. The most abundant non-neoplastic cell population in the GBM microenvironment is tumor-associated macrophages (TAMs). Of the GBM subtypes, MES expresses the highest levels of TAM-associated genes. Our analysis of TAM numbers revealed that MES GBM also has the highest number of TAMs compared to the other subtypes. When we correlated the high and low expression levels of TAM-associated genes with patient survival in a subtype-specific manner, only PN GBM patients showed a correlation of high expression: short survival and low expression: long survival. PN GBM is also known to be the most resistant to anti-neoplastic cell-specific targeted therapies. To examine TAM-GBM cell interactions, we used genetically engineered immunocompetent mouse models of PDGFB- and NF-1 loss- driven GBM and showed that tumor cells induce TAMs to produce the key pro-inflammatory cytokine IL-1β. TAMs release IL-1β, which binds to the receptor IL-1R1 on tumor cells and leads to activation of IL-1β signaling in PDGFB-driven GBM cells, which leads to i) increased stemness and growth, and ii) increased expression of the monocyte chemoattractant protein (MCP) network (CCL2, CCL7, CCL8, CCL12) in PDGFB- driven GBM cells. Our data showed that loss of IL-1β from the microenvironment resulted in a significant decrease in PDGFB-driven GBM formation and growth compared to wild-type mice in vivo. Based on our data, we hypothesize that TAM interaction with GBM cells is cell type- and subtype-specific and that they have different functions in PN and MES GBM subtypes. In this application, we will determine the detailed mechanism by which PN and MES GBM cells recruit and alter the function of macrophages to create specialized TAMs (Aim 1). To determine the mechanism of IL-1β signaling, the MCP network, and their downstream targets in PDGFB- and NF1 loss-driven GBM using genetically engineered mouse models and human GSC-derived tumors in vivo. Determine the mechanism by which TAMs and IL-1β support the creation and maintenance of the perivascular niche, which provides the proper microenvironment for glioma stem cells – the treatment-resistant population of glioma (Aim 3). The proposed studies will provide new mechanistic insights into fundamental cellular and molecular biological processes related to TAM– tumor cell interaction in vivo, and will allow for identification of novel potential therapeutic targets to glioblastoma.

项目摘要（摘要） 胶质母细胞瘤（GBM）是最常见和侵略性的原发性脑肿瘤。肿瘤的浸润性 细胞使手术切除不完整。此外，复发是不可避免的目的地辐射，并且 诊断后15个月内，替莫唑胺治疗和患者死亡。 GBM分为几个 基于不同基因表达谱的分子亚型，包括胸膜（PN），间充质（MES），，， 经典（CL）。当前的抗肿瘤疗法无法提供持久反应的一个重要原因 GBM是肿瘤微环境的适应性。最丰富的非肿瘤细胞种群 在GBM中，微环境是肿瘤相关的巨噬细胞（TAMS）。 GBM亚型的MES 表达最高水平的TAM相关基因。我们对TAM数字的分析表明，MES GBM 与其他亚型相比，TAM的数量也最高。当我们关联高和低 TAM相关基因与患者生存的表达水平仅以亚型特异性方式，仅PN GBM 患者表现出高表达的相关性：短生存率和低表达：长期生存。 PN GBM是 也已知是对抗塑性细胞特异性靶向疗法的最具耐药性。检查TAM-GBM 细胞相互作用，我们使用了PDGFB和NF-1损耗的一般设计的免疫能力小鼠模型 - 驱动的GBM并表明肿瘤细胞会诱导TAM产生关键的促炎细胞因子IL-1β。 TAM释放IL-1β，该IL-1β与受体IL-1R1在肿瘤细胞上结合，并导致IL-1β的激活 PDGFB驱动的GBM细胞中的信号传导，这导致i）升高和生长，ii）增加 PDGFB-中单核细胞化学吸引蛋白（MCP）网络（MCP）网络（CCL2，CCL7，CCL8，CCL12）的表达 驱动的GBM细胞。我们的数据表明，微环境中IL-1β的损失导致了显着的 与体内的野生型小鼠相比，PDGFB驱动的GBM形成和生长的减少。根据我们的数据， 我们假设TAM与GBM细胞的相互作用是细胞类型和亚型特异性的，并且它们具有 PN和MES GBM亚型的不同功能。在此应用程序中，我们将确定详细的 PN和MES GBM细胞募集和改变巨噬细胞功能以创建的机制 专业TAMS（AIM 1）。为了确定IL-1β信号的机理，MCP网络及其 PDGFB和NF1损耗驱动的GBM的下游目标使用一般设计的鼠标模型 和人类GSC衍生的肿瘤在体内。确定TAM和IL-1β支持的机制 血管周生境的创建和维护，可提供适当的微环境 对于神经胶质瘤干细胞 - 胶质瘤的耐药群体（AIM 3）。拟议的研究将 提供有关与TAM相关的基本细胞和分子生物学过程的新机械见解 体内肿瘤细胞相互作用，并将允许鉴定出新的潜在治疗靶标 胶质母细胞瘤。