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

• 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
• 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

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.

项目摘要 胶质母细胞瘤（GBM）是成人中最致命的脑癌形式。GBM患者的中位生存期为 仅在初次诊断后约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基因改变驱动的。然而，靶向治疗，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中总细胞的50 肿瘤块我们最近的研究表明，昼夜节律调节因子CLOCK/BMAL 1是一种癌基因， GBM在神经胶质瘤干细胞（GSC）中高度表达，其作用是通过增加GSC的自我更新， 代谢作用，并通过上调趋化因子嗅觉调节素样3（OLFML 3）将小胶质细胞招募到TME中 表达（Chen等人，Cancer Discovery，2020）。然而，OLFML 3如何在分子水平上 触发小胶质细胞浸润以及小胶质细胞如何影响免疫抑制和免疫治疗 尚未确定。因此，我们在这项研究中的总体目标是解决这一知识差距， 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OLFML 3传感器/受体或结合蛋白， 并确定其在CLOCK/BMAL 1高GBM中介导OLFML 3诱导的小胶质细胞浸润中的作用。在Aim中 2，我们将确定负责OLFML 1诱导的小胶质细胞的关键细胞内通路， 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对免疫疗法的原发性耐药性，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。我们建议采用综合战略 结合获得和丧失功能的方法，在体外和体内系统，以及蛋白质组学和 转录组学分析以测试每个目标。总之，这个项目将揭示小胶质细胞的新机制， 并揭示了新GBM免疫策略。