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：
9976205
负责人：
Peiwen Chen
金额：
$ 10.81万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
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 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9976205
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.

项目概要/摘要胶质母细胞瘤 (GBM) 是成人中最致命的脑癌，中位生存期为一年诊断。不幸的是，传统疗法和靶向疗法均未能改善 GBM 患者的生存率过去 40 年。肿瘤微环境（TME）中的免疫细胞遗传稳定，并且具有成为有希望的治疗靶点。肿瘤相关巨噬细胞/小胶质细胞（TAM）是最常见的丰富的免疫细胞浸润 GBM TME（可占活细胞总数的 50%），在促进肿瘤进展和诱导免疫治疗耐药性方面发挥重要作用。然而， TAM 靶向治疗或免疫治疗的前景在 GBM 中尚未实现，部分原因是对 GBM 中 TAM 行为和功能的分子机制了解有限。我在 DePinho 实验室的博士后工作揭示了控制巨噬细胞招募的新机制和小胶质细胞进入 GBM TME。值得注意的是，我确定通过靶向巨噬细胞/小胶质细胞浸润抑制赖氨酰氧化酶 (LOX) 或昼夜节律调节剂 CLOCK 代表了一种有前途的治疗方法 GBM（Chen 等人，Cancer Cell 2019；Chen 等人，Cancer Discovery，修订中）。招聘后，巨噬细胞/小胶质细胞表现出一系列表型，包括免疫刺激性 M1 表型和免疫抑制M2表型。众所周知，GBM 中的 TAM 通常极化为 M2 表型，将 TAM 从 M2 重编程为 M1 表型可能是一种有前途的治疗策略 GBM。我的初步研究表明，TANK 结合激酶 1 (TBK1) 在 GBM 中由 TAM 统一表达并且这种药物激酶可以控制 M1 和 M2 表型之间的巨噬细胞极化转换。巨噬细胞 TBK1 的遗传和药理学抑制会损害 M2 极化并抑制 GBM 多个 GBM 小鼠模型中的进展（Chen 等人，手稿正在准备中）。在K99阶段，这个该提案将进一步研究巨噬细胞TBK1在GBM中如何调节/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，因此在 R00 阶段，该提案将研究是否抑制 TAM 浸润（LOX 或 CLOCK 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阻断的抗肿瘤反应（ICB），即我将测试针对 TAM 和免疫检查点的潜在联合治疗策略 GBM。最后，拟议的研究将确定 TBK1 调节的 TAM 的关键因素，这些因素可能有助于 GBM 进展。我建议采用一种结合功能获得和功能丧失方法的综合策略，体外和体内系统，以及蛋白质组和转录组分析来识别和表征这些因素。该项目将共同揭示 GBM 进展的新机制并提供新的治疗方法 GBM 的目标。