Metabolic and molecular regulation of myeloid cell functions in brain cancer

脑癌中骨髓细胞功能的代谢和分子调控

• 批准号: 10637780
• 负责人: Filippo Veglia
• 金额: $ 46.44万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-15 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10637780
• 关键词: Animal Model; Anti-Inflammatory Agents; Automobile Driving; Avidity; Binding; CAR T cell therapy; Cell physiology; Cells; Clinical; Clinical Trials; Consumption; Data; Development; Endoplasmic Reticulum; Epigenetic Process; Exhibits; Exposure to; Genes; Genetic Transcription; Glioblastoma; Glioma; Glucose; Glycolysis; Goals; Histone Acetylation; Histones; Human; Hypoxia; Immune; Immunosuppression; Immunotherapy; In Vitro; Infiltration; Isotopes; Label; Link; Lysine; Macrophage; Maintenance; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of brain; Maps; Mediator; Metabolic; Microglia; Modification; Molecular; Myeloid Cells; Outcome; Patients; Phosphotransferases; Play; Production; Regulation; Resistance; Role; SLC2A1 gene; Signal Transduction; Specimen; System; T cell therapy; Testing; Therapeutic; Tissues; Treatment Efficacy; Tumor Immunity; Tumor-associated macrophages; Work; chimeric antigen receptor T cells; effective intervention; endoplasmic reticulum stress; gene induction; glucose metabolism; immunosuppressive macrophages; improved; in vivo; innovation; metabolomics; monocyte; multiple omics; neoplastic cell; novel; novel therapeutic intervention; novel therapeutics; programs; promoter; resistance mechanism; sensor; stressor; therapeutic evaluation; tumor; tumor-immune system interactions

Glioblastoma (GBM), the most aggressive and lethal form of brain cancer, is characterized by a profound immunosuppressive microenvironment (TME) that restricts the effects of promising immunotherapies. Therefore, there is a pressing need to develop more effective interventions to overcome this mechanism of resistance. Tumor associated macrophages (TAMs) are a mixture of monocyte-derived macrophages (MDM) and microglia (MG), and they are instrumental for the maintenance of the immunosuppressive state of GBM. However, there are no effective approaches to overcome the immunosuppressive activity of TAMs in GBM, mainly due to an incomplete understanding of TAM regulatory functions. Our long term-goal is to dissect targetable metabolic and molecular mechanisms regulating TAM functions in the context of GBM; as these discoveries will facilitate novel therapies to target immunosuppression and improve the dismaying outcome of GBM patients. A recent study demonstrated that TAM are major consumers of glucose and maintain a robust glucose metabolism in the TME. However, it has not yet been determined how GBM supports the adaptation to glucose metabolism in TAMs and the functional consequences of this adaptation also remain elusive. Endoplasmic reticulum (ER) stress activation is associated with the malignant progression of glioma and with the infiltration of anti-inflammatory macrophages. PKR-like ER kinase (PERK), a critical ER stress sensor, was found to be significantly activated in human glioma tissues, and its inhibition altered ATP/lactate production by glioma cells. Our preliminary data expanded these findings indicating that MDM demonstrated highest glucose avidity among MG and neoplastic cells in GBM tumors, and PERK was strongly activated in GBM infiltrating GLUT1+MDM. Contrary to MG, MDM exhibited potent immunosuppressive activity. GLUT1+MDM were the only contributors to the suppressive activity associated with MDM in GBM tumors. GBM-derived factors primed activation of PERK signaling in MDM, which correlated with metabolic reprogramming resulting in high glycolysis, immunosuppressive functions, histone lactylation, and no change in histone acetylation. Based on our crucial observations, we hypothesize that a PERK-driven perturbation of glucose metabolism in MDM governs their immunosuppressive functions via lactate-derived lactylation of histone lysine residues. We will test this hypothesis through the following aims: Aim1: to elucidate underlying mechanisms of how PERK governs glycolysis in MDM in GBM tumors; Aim2: to define glucose-driven epigenetic modifications that regulates immunosuppressive programs in MDM; Aim3: to investigate the therapeutic potential of an epigenetic targeting approach to modulate the functions of TAMs in GBM. The proposed studies are highly innovative because they will elucidate a previously uncharacterized link between ER stress and glucose metabolism that regulates the activity of TAMs via epigenetic mechanisms. Our proposal will provide a mechanistic rationale for the development of novel therapies to target immunosuppressive TAMs and enhance the efficacy of immunotherapy in GBM patients.

胶质母细胞瘤（GBM）是脑癌的最具侵略性和致命形式，其特征是深刻 免疫抑制微环境（TME）限制了有希望的免疫疗法的影响。所以， 迫切需要开发更有效的干预措施来克服这种抵抗机制。 肿瘤相关的巨噬细胞（TAM）是单核细胞衍生的巨噬细胞（MDM）和小胶质细胞的混合物 （mg），它们有助于维持GBM的免疫抑制状态。但是，那里 没有有效的方法来克服TAM在GBM中的免疫抑制活性，这主要是由于 对TAM调节功能的不完全理解。我们的长期目标是剖析可靶向的代谢和 在GBM背景下调节TAM功能的分子机制；这些发现将有助于小说 靶向免疫抑制并改善GBM患者令人沮丧的结果的疗法。最近的研究 证明TAM是葡萄糖的主要消费者，并在TME中保持强大的葡萄糖代谢。 但是，尚未确定GBM如何支持TAM中葡萄糖代谢的适应 而且这种适应的功能后果也仍然难以捉摸。内质网（ER）应力 激活与神经胶质瘤的恶性进展以及抗炎的浸润有关 巨噬细胞。发现PKR样ER激酶（PERK）是一种临界ER应力传感器，被发现显着激活 在人神经胶质瘤组织中，其抑制作用改变了神经胶质瘤细胞的ATP/乳酸产生。我们的初步数据 扩展了这些发现，表明MDM在MG和肿瘤中表现出最高的葡萄糖亲和力 GBM肿瘤中的细胞和PERK在GBM浸润GLUT1+MDM中被强烈激活。与MG相反，MDM 表现出有效的免疫抑制活性。 GLUT1+MDM是抑制活动的唯一贡献者 与GBM肿瘤中的MDM相关。 GBM衍生的因素启动了MDM中PERK信号的激活， 与代谢重编程相关，导致高糖酵解，免疫抑制功能，组蛋白 乳酸化，组蛋白乙酰化无变化。根据我们的关键观察，我们假设 MDM中葡萄糖代谢的PERK驱动扰动通过其免疫抑制功能通过 组蛋白赖氨酸残基的乳酸衍生乳酸化。我们将通过以下目的检验这一假设： AIM1：阐明振兴如何控制GBM肿瘤中MDM糖酵解的潜在机制； AIM2： 定义葡萄糖驱动的表观遗传修饰，以调节MDM中的免疫抑制程序； AIM3：研究表观遗传靶向方法调节功能的治疗潜力 GBM中的TAM。拟议的研究具有高度创新性，因为它们将阐明以前 ER应力与葡萄糖代谢之间的未表征联系，可以调节TAM的活性 表观遗传机制。我们的建议将为发展新颖的理由提供机械基本原理 靶向免疫抑制性TAM并增强免疫疗法在GBM患者中的疗效的疗法。