Targeting macrophage reprogramming in glioblastoma

胶质母细胞瘤中靶向巨噬细胞重编程

• 批准号: 10734257
• 负责人: Peiwen Chen
• 金额: $ 40.05万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10734257
• 关键词: Adult; Affect; CCL2 gene; CCL7 gene; Cell Culture Techniques; Cells; Clinical; Combined Modality Therapy; Cytometry; Data; Data Set; Diagnosis; Disease; Epigenetic Process; Exhibits; Family; Fees; Flow Cytometry; G-Protein-Coupled Receptors; Genetic; Genetically Engineered Mouse; Glioblastoma; Glioma; Goals; Growth; Immunofluorescence Immunologic; Immunotherapeutic agent; Impairment; In Vitro; Infiltration; Knockout Mice; Knowledge; Macrophage; Malignant neoplasm of brain; Mediating; Modeling; Molecular; Mus; Myeloid Cells; Pathway interactions; Patients; Phenotype; Population; Process; Proteomics; Role; Sampling; Signal Transduction; Solid Neoplasm; Specimen; Stat3 protein; System; Testing; The Cancer Genome Atlas; Therapeutic; Time; Translational Research; Tumor Promotion; Tumor-associated macrophages; Validation; druggable target; gain of function; in vivo; inhibitor; innovation; loss of function; monocyte; mouse model; novel; novel therapeutic intervention; patient derived xenograft model; peripheral blood; pharmacologic; pre-clinical; preclinical trial; programs; receptor; single-cell RNA sequencing; stemness; therapeutic target; transcriptome sequencing; transcriptomic profiling; transcriptomics; translational study; tumor; tumor microenvironment; tumor progression

Project Summary Glioblastoma is the most lethal form of primary brain cancer in adults with a median survival of approximately 14-16 months following diagnosis. In contrast to glioma cells, components of the tumor microenvironment (TME) of glioblastoma are genetically stable and are considering as the promising therapeutic targets. Tumor- associated macrophages (TAMs) are the most abundant cell population in the TME, which account for up to 50% of total cells in the entire glioblastoma tumor mass. Macrophages exhibit a spectrum of functions that span from an anti-tumor (known as M1) to a pro-tumor (known as M2) phenotype. TAMs are usually skewed toward a pro- tumor phenotype in glioblastoma. Given the predominance of these cells in glioblastoma, therapeutic strategies for their reprogramming to an anti-tumor phenotype is desirable. G protein-coupled receptors are a large family of receptors that are prominent pharmacological targets in biomedicine. Our preliminary data shows that G protein-coupled receptor 183 (GPR183) is highly expressed by TAMs in glioblastoma and may involve in TAM pro-tumor phenotype polarization. In this proposal, we will investigate whether and how GPR183 contributes to TAM pro-tumor phenotype polarization, reveal how such polarized TAMs promote tumor progression, and develop potential therapeutic strategies targeting TAM reprogramming in glioblastoma. To achieve these goals, we propose the following specific Aims: Aim 1. Clarify the role and underlying mechanism of GPR183 in TAM reprogramming in glioblastoma; Aim 2. Determine how GPR183-regulated TAM reprogramming promotes glioblastoma progression; and Aim 3. Basic to translational study: targeting TAM reprogramming using tumor samples and models from glioblastoma patients. 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 TAM reprogramming and reveal new immunotherapeutic strategies for glioblastoma.

项目摘要 胶质母细胞瘤是成人原发性脑癌中最致命的形式， 诊断后14-16个月。与神经胶质瘤细胞相反，肿瘤微环境（TME）的成分 胶质母细胞瘤的基因稳定，被认为是有希望的治疗靶点。肿瘤- 相关巨噬细胞（TAM）是TME中最丰富的细胞群，占TME的50%。 在整个胶质母细胞瘤肿瘤块中的细胞总数。宏程序展示了一系列功能，从 抗肿瘤（称为M1）到促肿瘤（称为M2）表型。一般来说，他们都倾向于亲- 胶质母细胞瘤的肿瘤表型。鉴于这些细胞在胶质母细胞瘤中的优势， 因为它们重编程为抗肿瘤表型是期望的。G蛋白偶联受体是一个大家族 受体是生物医学中重要的药理学靶点。初步数据显示，G 蛋白偶联受体183（GPR 183）在胶质母细胞瘤中由TAM高表达，可能参与TAM的形成 促肿瘤表型极化。在本提案中，我们将研究GPR 183是否以及如何有助于 TAM促肿瘤表型极化，揭示了这种极化的TAM如何促进肿瘤进展， 开发针对胶质母细胞瘤中TAM重编程的潜在治疗策略。为了实现这些目标， 我们提出以下具体目标：目标1。阐明GPR 183在TAM中的作用和潜在机制 胶质母细胞瘤中的重编程; Aim 2.确定GPR 183调节的TAM重编程如何促进 胶质母细胞瘤进展;和Aim 3.转化研究的基础：利用肿瘤靶向TAM重编程 从胶质母细胞瘤患者的样本和模型。我们建议采用综合战略相结合的增益- 和功能丧失的方法，体外和体内系统，以及蛋白质组学和转录组学分析 测试每个目标。总之，该项目将揭示TAM重编程的新机制，并揭示新的 胶质母细胞瘤的免疫策略。