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: 10265490
• 负责人: Dolores Hambardzumyan
• 金额: $ 49.83万
• 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/10265490
• 关键词: Affect; Anatomy; Animals; Antineoplastic Agents; Binding; Biological Process; Bone Marrow; CCL2 gene; CCL7 gene; CCL8 gene; Cell Communication; Cells; Chemotaxis; Complement; Data; Diagnosis; Diffuse intrinsic pontine glioma; Excision; Gene Expression; Genes; Genetic Engineering; Genetically Engineered Mouse; Glioblastoma; Glioma; Goals; Growth; Growth Factor; Human; IL1R1 gene; Immunocompetent; Immunotherapy; In Vitro; Inflammation; Inflammatory; Interleukin-1 beta; Intervention; Knock-out; Knockout Mice; Location; Magnetic Resonance Imaging; Maintenance; Mesenchymal; Microglia; Modality; Modeling; Molecular; Monocyte Chemoattractant Proteins; Mus; NF1 gene; Natural Immunity; Nature; Oncogenic; Operative Surgical Procedures; PDGFB gene; PDGFRB gene; Patients; Phenotype; Play; Population; Primary Brain Neoplasms; Primary Neoplasm; Production; Prognosis; Proteins; Radiation; Radiation therapy; Recombinants; Recurrence; Resistance; Role; Signal Transduction; Slice; Survival Rate; Tetanus Helper Peptide; The Cancer Genome Atlas; Therapeutic; Translating; Tumor-Derived; Tumor-associated macrophages; Wild Type Mouse; Work; Xenograft procedure; base; cell type; cytokine; design; genetic approach; genetic signature; genetically modified cells; human disease; improved; in vivo; in vivo Model; insight; knockout animal; macrophage; migration; molecular subtypes; mouse model; neoplastic cell; neutralizing antibody; novel; novel therapeutics; overexpression; patient derived xenograft model; public health relevance; receptor; recruit; response; small hairpin RNA; stem cell therapy; stem cells; stemness; targeted treatment; temozolomide; therapeutic target; treatment response; tumor; tumor initiation; tumor microenvironment; tumor progression

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）是最常见和最具侵袭性的原发性脑肿瘤。肿瘤的浸润性 细胞使手术切除不完全。此外，尽管进行了放射治疗， 替莫唑胺治疗和患者在诊断后15个月内死亡。GBM分为几种 基于不同基因表达谱的分子亚型，包括前神经（PN），间充质（MES）， 经典（CL）。目前的抗肿瘤治疗不能提供持久的反应的一个重要原因是， GBM是肿瘤微环境的适应性。最丰富的非肿瘤细胞群 在GBM微环境中的是肿瘤相关巨噬细胞（TAM）。在GBM亚型中，MES 表达最高水平的TAM相关基因。我们对TAM数据的分析显示，MES GBM 与其他亚型相比，也具有最高数量的TAM。当我们把高和低 TAM相关基因的表达水平以亚型特异性方式与患者生存期相关，仅PN GBM 患者表现出高表达：短生存期和低表达：长生存期的相关性。PN GBM是 也已知对抗肿瘤细胞特异性靶向治疗最有抗性。检查TAM-GBM 细胞相互作用，我们使用PDGFB和NF-1缺失的基因工程免疫活性小鼠模型， 驱动GBM，并显示肿瘤细胞诱导TAM产生关键的促炎细胞因子IL-1β。 TAM释放IL-1β，其与肿瘤细胞上的受体IL-1 R1结合并导致IL-1β活化 在PDGFb驱动的GBM细胞中的信号传导，其导致i）增加的干性和生长，和ii）增加的 单核细胞趋化蛋白（MCP）网络（CCL 2、CCL 7、CCL 8、CCL 12）在PDGFB-L1中的表达 驱动GBM细胞。我们的数据表明，IL-1β从微环境中的丢失导致了显著的 与体内野生型小鼠相比，PDGFB驱动的GBM形成和生长减少。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， PN和MES GBM亚型的不同功能。在这个应用程序中，我们将确定详细的 PN和MES GBM细胞招募和改变巨噬细胞功能的机制， 专门的TAM（目标1）。为了确定IL-1β信号转导机制，MCP网络，以及它们的相互作用， 使用基因工程小鼠模型在PDGFB和NF 1丢失驱动的GBM中的下游靶点 和人GSC衍生的肿瘤。确定TAM和IL-1β支持 血管周围小生境的形成和维持，提供适当的微环境 对于胶质瘤干细胞-胶质瘤的治疗抗性群体（Aim 3）。拟议的研究将 为与TAM相关的基本细胞和分子生物学过程提供新的机制见解- 肿瘤细胞在体内的相互作用，并将允许识别新的潜在的治疗靶点， 胶质母细胞瘤