Metabolic interactions between tumor cells and the immunce system in GBM A potential Achilles heel of GBM for novel therapeutics

GBM 中肿瘤细胞与免疫系统之间的代谢相互作用是 GBM 新疗法的潜在致命弱点

• 批准号: 10522529
• 负责人: Loic Pierre Deleyrolle
• 金额: $ 42.33万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10522529
• 关键词: Affect; Apolipoprotein E; Apoptosis; Biology; Brain Neoplasms; C57BL/6 Mouse; Cell Compartmentation; Cell Cycle; Cell Lineage; Cell Shape; Cell physiology; Cells; Cellular Metabolic Process; Cellular biology; Clinical; Communication; Complex; Coupled; Dependence; Disease; Disease Outcome; Disease Progression; Environment; Exhibits; FABP3 gene; Fatty Acids; Flow Cytometry; Genetic; Glioblastoma; Glioma; Glucose; Goals; Growth; Heterogeneity; Image; Immune; Immune checkpoint inhibitor; Immune system; Immunological Models; In Vitro; Intervention; Investigation; Knockout Mice; LCN2 gene; Label; Laboratories; Link; Lipids; Logic; Maintenance; Malignant Neoplasms; Mediating; Metabolic; Mitochondria; Modeling; Molecular; Morbidity - disease rate; Mus; Myeloid-derived suppressor cells; Nature; Outcome; Oxidative Phosphorylation; Pathway interactions; Patients; Pharmacology; Phenotype; Play; Population; Proliferating; Recurrence; Regulatory T-Lymphocyte; Reporting; Research Design; Resistance; Role; Shapes; Signal Transduction; Specimen; System; T-Lymphocyte; Technology; Testing; Therapeutic; Therapeutic Effect; Time; Transgenic Mice; Translating; Tumor Immunity; Tumor-infiltrating immune cells; Work; adipokines; aerobic glycolysis; anti-PD1 therapy; atorvastatin; base; cancer cell; cancer therapy; chemotherapy; clinically relevant; comparative; cytokine; digital; experimental study; genomic profiles; immune checkpoint; improved; in vivo; insight; intercellular communication; lipid biosynthesis; lipid metabolism; lipid transport; macrophage; mortality; neoplastic cell; novel therapeutics; programs; recruit; single-cell RNA sequencing; standard of care; temozolomide; therapeutic evaluation; therapy resistant; transcriptomics; tumor; tumor heterogeneity; tumor microenvironment; tumor progression; tumor-immune system interactions; tumorigenic; uptake

ABSTRACT Background: We recently revealed that glioblastoma (GBM) contain cell populations with distinct metabolic requirements, with fast-cycling cells (FCCs) harnessing aerobic glycolysis, and treatment-resistant slow-cycling cells (SCCs) preferentially engaging lipid metabolism. How the different tumor cells interact with immune cells and how this metabolic heterogeneity shapes the immune landscape in GBM has yet to be understood. Objectives/Hypothesis: The objectives of this study are to understand the mechanisms of communication in the tumor microenvironment, specifically to characterize the metabolic interactions between SCCs (a therapeutically resistant population that drive disease progression and recurrence) and the immune compartment. Here, we will investigate a model of intercellular communication within GBM where SCCs shape an immunosuppressive tumor milieu, which in turn assume metabolic support to SCCs by providing them with lipids, which are essential for SCC metabolism and function. Importantly, we will test multiple genetic and clinically amenable pharmacological approaches disrupting this metabolic interplay to antagonize GBM. Specific aims: Our specific aims will be 1) Dissect the relationship of SCCs with the tumor microenvironment, 2) Delineate how recruited immune suppressive cell mediate SCC-driven tumor progression, and 3) Establish that immune infiltrates provide metabolic support to SCCs by providing lipids. Study design: The link between tumor heterogeneity and tumor immune landscape in GBM will be deciphered with specific investigations of the metabolic interplay taking place between these cellular compartments. In aim 1, we will delineate the cell lineage (SCC vs FCC) relationship with immune infiltrates by investigating their genomic profile and spatial organization, using single cell RNA sequencing technology and GeoMx Digital Spatial Profiling, respectively. We will also evaluate the role of the specific adipokine, Lipocalin-2, in shaping the immune microenvironment. In aim 2 we will employ multiple approaches disrupting the macrophage, myeloid- derived suppressor cell, and regulatory T cell compartments, and compare the effect on survival, growth and chemotherapy sensitivity of SCCs and FCCs. In aim 3 the use of fluorescently labeled lipids combined with flow cytometry and time lapse imaging will enable the comparison of lipid transfer between immune cells, FCCs and SCCs. Finally, in vivo experiments will test the hypothesis that targeting lipid trafficking (inhibition of FABP3 or ApoE) or lipogenesis (statin treatment) provide therapeutic benefits by affecting SCCs and rendering the overall tumor more responsive to chemotherapy. Based on the recently reported synergistic effect of statins with immune checkpoint inhibitors, we will also evaluate the combination of statins with anti PD-1 therapy. Impact: Successfully completed, this project will validate therapeutically amenable approaches targeting metabolic communication to improve brain tumor associated morbidity and mortality.

抽象的 背景：我们最近发现胶质母细胞瘤（GBM）包含具有不同代谢特征的细胞群 要求，利用有氧糖酵解的快速循环细胞（FCC）和抗治疗的慢循环细胞 细胞（SCC）优先参与脂质代谢。不同的肿瘤细胞如何与免疫细胞相互作用 这种代谢异质性如何影响 GBM 的免疫景观尚待了解。 目标/假设：本研究的目的是了解沟通机制 肿瘤微环境，特别是表征 SCC 之间的代谢相互作用（a 导致疾病进展和复发的治疗耐药人群）和免疫区室。 在这里，我们将研究 GBM 内的细胞间通讯模型，其中 SCC 形成 免疫抑制肿瘤环境，反过来又通过为鳞状细胞提供脂质来为它们提供代谢支持， 这对于鳞状细胞癌的代谢和功能至关重要。重要的是，我们将测试多种基因和临床 合适的药理学方法可以破坏这种代谢相互作用，从而拮抗 GBM。 具体目标：我们的具体目标是1）剖析SCC与肿瘤微环境的关系， 2) 描述招募的免疫抑制细胞如何介导 SCC 驱动的肿瘤进展，以及 3) 建立 免疫浸润通过提供脂质为鳞状细胞癌提供代谢支持。 研究设计：GBM 中肿瘤异质性与肿瘤免疫景观之间的联系将被破译 对这些细胞区室之间发生的代谢相互作用进行具体研究。 在目标 1 中，我们将通过调查来描绘细胞谱系（SCC 与 FCC）与免疫浸润的关系 使用单细胞 RNA 测序技术和 GeoMx Digital 分析其基因组概况和空间组织 分别进行空间剖析。我们还将评估特定脂肪因子 Lipocalin-2 在塑造 免疫微环境。在目标 2 中，我们将采用多种方法破坏巨噬细胞、骨髓细胞 衍生的抑制细胞和调节性 T 细胞区室，并比较对生存、生长和 SCC 和 FCC 的化疗敏感性。在目标 3 中，使用荧光标记的脂质与流动相结合 细胞计数和延时成像将能够比较免疫细胞、FCC 和 SCC。最后，体内实验将检验针对脂质运输（抑制 FABP3 或 ApoE）或脂肪生成（他汀类药物治疗）通过影响 SCC 并呈现整体效果来提供治疗益处 肿瘤对化疗更敏感。基于最近报道的他汀类药物与免疫的协同作用 检查点抑制剂，我们还将评估他汀类药物与抗 PD-1 疗法的组合。 影响：成功完成后，该项目将验证针对目标的治疗方法 代谢通讯可改善脑肿瘤相关的发病率和死亡率。