Mechanism and therapeutic potential of macrophage regulation in glioblastoma

巨噬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：
10469658
负责人：
Peiwen Chen
金额：
$ 24.9万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-08 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10469658
关键词：
Adult Affect Behavior Binding C57BL/6 Mouse Cells Combination immunotherapy Combined Modality Therapy Cytometry DNA Binding Data Diagnosis Exhibits Fibrinogen Genetic Glioblastoma HIF1A gene Hypoxia IGF1 gene IL4 gene Immune Immunotherapy Impairment In Vitro Infiltration Interleukin-13 Malignant Neoplasms Malignant neoplasm of brain Manuscripts Mediating Microarray Analysis Microglia Modeling Molecular PD-1/PD-L1 PTEN gene Pathway interactions Patients Pharmacology Phase Phenotype Phosphotransferases Preparation Protein-Lysine 6-Oxidase Proteomics Regulation Resistance Role SCID Mice Sampling Series Signal Pathway System T-Cell Depletion TANK-binding kinase 1 Testing Therapeutic Therapeutic Trials Time Transcriptional Regulation Tumor-associated macrophages Tumor-infiltrating immune cells Work anti-PD1 therapy antitumor effect cancer cell chemokine circadian conventional therapy cytokine genetic approach immune checkpoint immune checkpoint blockade improved in vivo innovation insight knock-down loss of function macrophage mouse model new therapeutic target novel pre-clinical promoter recruit single cell sequencing targeted treatment therapeutic target transcription factor transcriptomics tumor tumor growth tumor microenvironment tumor progression

项目摘要

Project Summary/Abstract Glioblastoma (GBM) is the most lethal form of brain cancer in adults, with a median survival of one year following diagnosis. Unfortunately, both conventional and targeted therapies have failed to improve GBM patient survival over the last 40 years. Immune cells in the tumor microenvironment (TME) are genetically stable, and have emerged as promising therapeutic targets. Tumor-associated macrophages/microglia (TAMs) are the most abundant immune cells infiltrating the GBM TME (which can account for up to 50% of total live cells), where they exhibit an important role in promoting tumor progression and inducing immunotherapy resistance. However, the promise of TAM-targeted therapy or immunotherapy in general has not yet been realized in GBM, due in part to a limited understanding of the molecular mechanisms underlying TAM behavior and function in GBM. My postdoctoral work in the DePinho lab revealed novel mechanisms governing the recruitment of macrophages and microglia into the GBM TME. Notably, I determined that targeting macrophage/microglia infiltration via inhibition of lysyl oxidase (LOX) or circadian regulator CLOCK represents a promising therapeutic approach for GBM (Chen et al., Cancer Cell 2019; Chen at al., Cancer Discovery, under revision). Upon recruitment, macrophages/microglia exhibit a spectrum of phenotypes, including the immunostimulatory M1 phenotype and immunosuppressive M2 phenotype. It is well known that TAMs in GBM are usually polarized toward an M2 phenotype, and reprogramming TAMs from M2 to M1 phenotype could be a promising therapeutic strategy for GBM. My preliminary studies show that TANK binding kinase 1 (TBK1) is uniformly expressed by TAMs in GBM and that this druggable kinase can control macrophage polarization switch between M1 and M2 phenotypes. Both genetic and pharmacological inhibition of macrophage TBK1 impaired M2 polarization and inhibited GBM progression in multiple GBM mouse models (Chen et al., manuscript in preparation). In the K99 phase, this proposal will further investigate how macrophage TBK1 is regulated/activated in GBM and how TBK1 controls macrophage M2 polarization. Since TAMs are immune suppressive cells, in the R00 phase this proposal will investigate whether inhibition of TAM infiltration (LOX or CLOCK inhibition) and/or M2 polarization (inhibition of TBK1 and its related signaling pathways) can alter anti-tumor responsiveness to immune checkpoint blockade (ICB), i.e., I will test potential combination therapeutic strategies targeting TAMs and immune checkpoints in GBM. Finally, the proposed studies will identify the key factors from TBK1-regulated TAMs which might contribute GBM progression. I propose to employ an integrated strategy combining gain- and loss-of-function approaches, in vitro and in vivo systems, as well as proteomic and transcriptomic analysis to identify and characterize these factors. Together, this project will uncover novel mechanisms of GBM progression and offer new therapeutic targets for GBM.

项目摘要/摘要胶质母细胞瘤（GBM）是成年人中最致命的脑癌形式，其中位生存期为一年诊断。不幸的是，常规疗法和靶向疗法都无法改善GBM患者的生存在过去的40年中。肿瘤微环境（TME）中的免疫细胞在遗传上是稳定的，并且具有成为有前途的治疗靶标。肿瘤相关的巨噬细胞/小胶质细胞（TAM）最多丰富的免疫细胞渗入GBM TME（最多可以占活细胞的50％），在促进肿瘤进展和诱导免疫疗法耐药性方面表现出重要作用。但是，在GBM中，尚未实现TAM靶向治疗或免疫疗法的承诺，部分原因是对GBM中TAM行为和功能的分子机制的有限理解。我在Depinho实验室中的博士后工作揭示了统治巨噬细胞的新机制小胶质细胞进入GBM TME。值得注意的是，我确定针对巨噬细胞/小胶质细胞浸润抑制赖氨酸氧化酶（LOX）或昼夜节律调节器时钟是一种有希望的治疗方法 GBM（Chen等人，癌细胞，2019年； Al。的Chen，Cancer Discovery，Revision）。招募时，巨噬细胞/小胶质细胞表现出各种表型，包括免疫刺激的M1表型和免疫抑制M2表型。众所周知，GBM中的TAM通常朝向M2极化表型和从M2到M1表型的重编程TAM可能是有希望的治疗策略 GBM。我的初步研究表明，储罐结合激酶1（TBK1）在GBM中均匀地表达并且这种可药物激酶可以控制M1和M2表型之间的巨噬细胞极化切换。巨噬细胞TBK1的遗传和药理抑制受损的M2极化并抑制GBM 多种GBM小鼠模型的进展（Chen等人，手稿制备）。在K99阶段，这个提案将进一步研究巨噬细胞TBK1如何在GBM中调节/激活以及TBK1如何控制巨噬细胞M2极化。由于TAM是免疫抑制细胞，在R00期，此建议将研究抑制TAM浸润（LOX或时钟抑制）和/或M2极化（抑制 TBK1及其相关信号通路）可以改变对免疫检查点封锁的抗肿瘤反应性（ICB），即，我将测试针对TAM和免疫检查点的潜在组合治疗策略 GBM。最后，拟议的研究将确定来自TBK1调节的TAM的关键因素，这可能有助于 GBM进展。我建议采用联合策略，结合了功能丧失方法，体外和体内系统，以及蛋白质组学和转录组分析，以识别和表征这些因素。该项目一起将发现GBM进展的新型机制，并提供新的治疗方法 GBM的目标。