Mechanism and therapeutic potential of microglia regulation in glioblastoma

小胶质细胞调节胶质母细胞瘤的机制和治疗潜力

基本信息

批准号：
10517137
负责人：
Peiwen Chen
金额：
$ 40万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10517137
关键词：
ARNTL gene Address Adult Affect Antibodies Binding Proteins Biological Assay CD8-Positive T-Lymphocytes CTLA4 gene Cell Count Cells Characteristics Clinic Co-Immunoprecipitations Combined Modality Therapy Complex Cytometry Data Development Diagnosis Failure Genetic Genetic Heterogeneity Genetically Engineered Mouse Genomics Glioblastoma Glioma Goals Growth Heterogeneity Immune checkpoint inhibitor Immunosuppression Immunotherapeutic agent Immunotherapy Impairment In Vitro Infiltration Integrins Knowledge Malignant Neoplasms Malignant neoplasm of brain Mass Spectrum Analysis Mediating Membrane Proteins Metabolic Microglia Molecular Oncogenes Pathway interactions Patients Pharmacology Phase Population Protein Array Proteomics Receptor Protein-Tyrosine Kinases Regulation Resistance Role SYK gene Sampling Signal Pathway Signal Transduction Subgroup System Testing Therapeutic Validation anti-CTLA4 anti-PD-1 anti-PD1 therapy anti-tumor immune response base cell motility chemokine circadian cytokine density effective therapy in vivo innovation loss of function macrophage migration mouse model neoplastic cell novel novel strategies novel therapeutic intervention olfactomedin patient derived xenograft model preclinical trial programmed cell death ligand 1 receptor recruit release of sequestered calcium ion into cytoplasm sensor single-cell RNA sequencing stem cell self renewal stem cells success targeted treatment therapeutic target transcriptomics treatment strategy tumor tumor microenvironment tumor progression

项目摘要

Project Summary Glioblastoma (GBM) is the most lethal form of brain cancer in adults. The median survival of GBM patients is only about 14-16 months after initial diagnosis. Genomic profiling has stratified GBM into various subgroups, which are driven by specific genetic alternations of core signaling pathways. However, targeted therapies, such as therapies against receptor tyrosine kinase signaling, have failed in the clinic. Tumor-cell genetic heterogeneity is one of the main reasons for this failure. In contrast, the tumor microenvironment (TME) of GBM is genetically stable, and are considering as the promising therapeutic targets. Tumor-associated microglia and macrophages (TAMs) are the most abundant cell population in the TME, which account for up to 50% of total cells in the GBM tumor mass. Our recent studies have demonstrated that circadian regulator CLOCK/BMAL1 is an oncogene in GBM and highly expressed in glioma stem cells (GSCs), which acts to increase GSC self-renewal through metabolic effects, and recruit microglia into the TME by upregulating chemokine olfactomedin-like 3 (OLFML3) expression (Chen et al., Cancer Discovery, 2020). However, the underlying molecular basis for how OLFML3 triggers microglial infiltration and subsequently how microglia affect immunosuppression and immunotherapy has yet to be determined. Thus, our overall goal in this study is to address this knowledge gap, and in so doing will develop potential therapeutic strategies targeting microglia for treating GBM. To achieve these goals, we propose three specific Aims. In Aim 1, we will identify OLFML3 sensor/receptor or binding protein in microglia, and determine its role in mediating OLFML3-induced microglial infiltration in CLOCK/BMAL1-high GBM. In Aim 2, we will determine the key microglial intracellular pathways that are responsible for OLFML1-induced microglial migration and GBM progression. In Aim 3, we will investigate whether inhibition of microglial infiltration can reverse primary resistance to immunotherapy in GBM, thus developing novel therapeutic strategies combining inhibition of microglia infiltration with immune checkpoint inhibitors. We propose to employ integrated strategies combining gain- and loss-of-function approaches, in vitro and in vivo systems, as well as proteomic and transcriptomic analysis to test each Aim. Together, this project will uncover novel mechanisms for microglial infiltration and reveal new immunotherapeutic strategies for GBM.

项目概要胶质母细胞瘤（GBM）是成人中最致命的脑癌。 GBM 患者的中位生存期为初次诊断后仅约 14-16 个月。基因组分析将 GBM 分为不同的亚组，这是由核心信号通路的特定遗传改变驱动的。然而，靶向治疗，例如作为针对受体酪氨酸激酶信号传导的疗法，在临床上已经失败。肿瘤细胞遗传异质性是这次失败的主要原因之一。相比之下，GBM 的肿瘤微环境 (TME) 在遗传上是稳定，被认为是有前途的治疗靶点。肿瘤相关小胶质细胞和巨噬细胞 (TAM) 是 TME 中最丰富的细胞群，占 GBM 细胞总数的 50% 肿瘤块。我们最近的研究表明，昼夜节律调节因子 CLOCK/BMAL1 是一种致癌基因。 GBM 并在神经胶质瘤干细胞 (GSC) 中高表达，可通过以下方式增强 GSC 的自我更新：代谢效应，并通过上调趋化因子 olfactomedin-like 3 (OLFML3) 将小胶质细胞招募到 TME 中表达（Chen 等人，Cancer Discovery，2020）。然而，OLFML3 的潜在分子基础触发小胶质细胞浸润以及随后小胶质细胞如何影响免疫抑制和免疫治疗尚未确定。因此，我们这项研究的总体目标是解决这一知识差距，并这样做将开发针对小胶质细胞治疗 GBM 的潜在治疗策略。为了实现这些目标，我们提出三个具体目标。在目标 1 中，我们将鉴定小胶质细胞中的 OLFML3 传感器/受体或结合蛋白，并确定其在介导 CLOCK/BMAL1 高 GBM 中 OLFML3 诱导的小胶质细胞浸润中的作用。瞄准 2、我们将确定导致OLFML1诱导小胶质细胞形成的关键小胶质细胞内途径迁移和 GBM 进展。在目标 3 中，我们将研究抑制小胶质细胞浸润是否可以逆转 GBM 对免疫治疗的主要耐药性，从而开发新的治疗策略用免疫检查点抑制剂抑制小胶质细胞浸润。我们建议采用综合策略结合功能获得和功能丧失方法、体外和体内系统以及蛋白质组学和转录组分析来测试每个目标。该项目将共同揭示小胶质细胞的新机制浸润并揭示 GBM 的新免疫治疗策略。