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Targeting macrophage reprogramming in glioblastoma

胶质母细胞瘤中靶向巨噬细胞重编程

基本信息

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
项目类别：
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

项目摘要

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.

项目概要胶质母细胞瘤是成人中最致命的原发性脑癌，中位生存期约为诊断后 14-16 个月。与神经胶质瘤细胞相比，肿瘤微环境 (TME) 的组成部分胶质母细胞瘤基因稳定，被认为是有希望的治疗靶点。瘤- 相关巨噬细胞 (TAM) 是 TME 中最丰富的细胞群，占 TME 的 50% 整个胶质母细胞瘤肿瘤块中的总细胞数。巨噬细胞表现出一系列功能，包括抗肿瘤（称为 M1）表型到促肿瘤（称为 M2）表型。 TAM 通常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占主导地位，治疗策略因为它们被重编程为抗肿瘤表型是可取的。 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。我们的初步数据表明，G 蛋白偶联受体 183 (GPR183) 在胶质母细胞瘤中由 TAM 高表达，并可能参与 TAM 促肿瘤表型极化。在本提案中，我们将研究 GPR183 是否以及如何有助于 TAM 促肿瘤表型极化，揭示这种极化的 TAM 如何促进肿瘤进展，以及开发针对胶质母细胞瘤 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 GPR183 在 TAM 中的作用和潜在机制胶质母细胞瘤中的重编程；目标 2. 确定 GPR183 调节的 TAM 重编程如何促进胶质母细胞瘤进展；目标 3. 转化研究基础：利用肿瘤靶向 TAM 重编程来自胶质母细胞瘤患者的样本和模型。我们建议采用综合策略，结合增益和功能丧失方法、体外和体内系统以及蛋白质组和转录组分析测试每个目标。该项目将共同揭示 TAM 重编程的新机制并揭示新的胶质母细胞瘤的免疫治疗策略。