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）是脑癌中最具侵袭性和致命性的一种，其特征在于深刻的 免疫抑制微环境（TME）限制了有前途的免疫疗法的效果。因此，我们认为， 迫切需要制定更有效的干预措施，以克服这种抗药性机制。 肿瘤相关巨噬细胞（tumor associated macrophages，TAM）是单核细胞源性巨噬细胞（monocyte-derived macrophages，MDM）和小胶质细胞的混合物 (MG)并且它们有助于维持GBM的免疫抑制状态。但 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监管功能的不完全理解。我们的长期目标是解剖目标代谢和 在GBM的背景下调节TAM功能的分子机制;因为这些发现将促进新的 靶向免疫抑制和改善GBM患者令人沮丧的结果的治疗。最近的一项研究 表明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对葡萄糖代谢的适应 这种适应的功能性后果也仍然难以捉摸。内质网应激 激活与胶质瘤的恶性进展和抗炎因子的浸润有关。 巨噬细胞PKR样ER激酶（PERK）是一种重要的ER应激感受器， 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和肿瘤中表现出最高的葡萄糖亲和力。 GBM肿瘤中的细胞，并且PERK在浸润GLUT 1 +MDM的GBM中被强烈激活。与MG、MDM相反 表现出有效的免疫抑制活性。GLUT 1 +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信号传导的激活， 与代谢重编程相关，导致高糖酵解，免疫抑制功能，组蛋白 组蛋白乙酰化没有变化。根据我们的关键观察，我们假设 PERK驱动的MDM葡萄糖代谢紊乱通过以下途径控制其免疫抑制功能： 组蛋白赖氨酸残基的乳酸盐衍生的乳酸化。我们将通过以下目标来检验这一假设： 目的1：阐明PERK如何控制GBM肿瘤中MDM的糖酵解的潜在机制;目的2： 确定在MDM中调节免疫抑制程序的葡萄糖驱动的表观遗传修饰; 目的3：探讨表观遗传靶向方法调节功能的治疗潜力。 GBM中的TAM。拟议的研究是高度创新的，因为它们将阐明一个以前的 ER应激和葡萄糖代谢之间的未表征的联系，其通过以下途径调节TAM的活性： 表观遗传机制。我们的建议将为小说的发展提供一个机械的理论基础。 靶向免疫抑制性TAM并增强免疫疗法在GBM患者中的功效的疗法。