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) 是最具侵袭性和致命性的脑癌，其特点是 免疫抑制微环境（TME）限制了有前景的免疫疗法的效果。所以， 迫切需要制定更有效的干预措施来克服这种抵抗机制。 肿瘤相关巨噬细胞 (TAM) 是单核细胞源性巨噬细胞 (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。然而，有 目前还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 监管功能的理解不完全。我们的长期目标是剖析目标代谢和 GBM 背景下调节 TAM 功能的分子机制；因为这些发现将促进新颖的 针对免疫抑制并改善 GBM 患者令人沮丧的结果的疗法。最近的一项研究 证明 TAM 是葡萄糖的主要消耗者，并在 TME 中维持稳健的葡萄糖代谢。 然而，尚未确定 GBM 如何支持 TAM 中葡萄糖代谢的适应 这种适应的功能后果也仍然难以捉摸。内质网 (ER) 应激 激活与神经胶质瘤的恶性进展以及抗炎细胞的浸润有关。 巨噬细胞。 PKR 样 ER 激酶 (PERK) 是一种关键的 ER 应激传感器，被发现被显着激活 在人类神经胶质瘤组织中，其抑制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 和肿瘤患者中表现出最高的葡萄糖亲和力 GBM 肿瘤中的细胞，PERK 在 GBM 浸润的 GLUT1+MDM 中被强烈激活。与 MG 相反，MDM 表现出强大的免疫抑制活性。 GLUT1+MDM 是抑制活性的唯一贡献者 与 GBM 肿瘤中的 MDM 相关。 GBM 衍生因子引发了 MDM 中 PERK 信号的激活， 与导致高糖酵解、免疫抑制功能、组蛋白的代谢重编程相关 乳酰化，组蛋白乙酰化没有变化。根据我们的重要观察，我们假设 MDM 中 PERK 驱动的葡萄糖代谢扰动通过以下方式控制其免疫抑制功能 组蛋白赖氨酸残基的乳酸衍生的乳酰化。我们将通过以下目标来检验这一假设： 目标 1：阐明 PERK 如何控制 GBM 肿瘤 MDM 糖酵解的潜在机制；目标2： 定义葡萄糖驱动的表观遗传修饰，调节 MDM 中的免疫抑制程序； 目标3：研究表观遗传靶向方法调节功能的治疗潜力 GBM 中的 TAM 数量。拟议的研究具有高度创新性，因为它们将阐明以前的研究 ER 应激和葡萄糖代谢之间未表征的联系通过调节 TAM 的活性 表观遗传机制。我们的建议将为新颖的开发提供机械原理 针对免疫抑制 TAM 的疗法并增强 GBM 患者免疫治疗的疗效。