Influence of glucose heterogeneity on the tumor immune landscape

葡萄糖异质性对肿瘤免疫景观的影响

• 批准号: 10533689
• 负责人: Claudio Scafoglio
• 金额: $ 13.25万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10533689
• 关键词: Active Biological Transport; Affinity; African American; Antigen-Presenting Cells; Antitumor Response; Area; Automobile Driving; Blood Vessels; Brain; CD3 Antigens; Cancer Etiology; Caucasians; Cell Line; Cell Separation; Cell membrane; Cell physiology; Cells; Cessation of life; Combination immunotherapy; Consumption; Coupled; Cytometry; Disease; Engineering; Epithelial Cells; Extracellular Fluid; Glucose; Glucose Transporter; Glycolysis; Goals; Growth; Heterogeneity; Histocompatibility Antigens Class I; Hypoxia; Immune; Immunologic Surveillance; Immunophenotyping; Immunosuppression; Interferon Type II; Investigation; Kidney; Label; Lactic acid; Lesion; Leukocytes; Link; Lung; Lung Adenocarcinoma; Malignant Neoplasms; Malignant neoplasm of brain; Malignant neoplasm of lung; Malignant neoplasm of pancreas; Malignant neoplasm of prostate; Measures; Mediating; Metabolic; Metabolic dysfunction; Metabolism; Molecular; Myeloid-derived suppressor cells; Na(+)-K(+)-Exchanging ATPase; Nutrient; Oncology; Oxidative Phosphorylation; Pathway interactions; Pharmaceutical Preparations; Phenotype; Physiological; Population; Positioning Attribute; Positron-Emission Tomography; Process; Production; Property; Pump; Regulatory T-Lymphocyte; Reporting; Research; Role; SLC2A1 gene; Shapes; Signal Transduction; Smoker; Sodium; T-Cell Proliferation; T-Lymphocyte; Testing; Time; Tracer; Tritium; Tumor-Derived; Tumor-Infiltrating Lymphocytes; Tumor-infiltrating immune cells; Up-Regulation; Urine; Warburg Effect; Woman; Work; advanced disease; anti-tumor immune response; cancer cell; carcinogenesis; cell type; cost; deprivation; design; extracellular; fluorodeoxyglucose; glucose metabolism; glucose transport; glucose uptake; improved; in vivo; insight; interest; macrophage; men; monocyte; never smoker; novel; overexpression; premalignant; repair strategy; tomography; treatment strategy; tumor; tumor metabolism; tumor microenvironment; tumor-immune system interactions; tumorigenic; uptake

Project Summary Lung cancer is the leading cause of cancer-related deaths worldwide and second most common cancer in both men and women. African American men are ~15 % more likely to develop lung cancer than their Caucasian counterparts. Lung adenocarcinoma is the most common type of lung cancer in both smokers and never smokers, and accounts for ~30 % of all cases. Treatment of lung cancer is moving towards drugs that specifically target aberrant pathways involved in carcinogenesis. One such area of interest is the metabolic dysfunction, specifically the upregulation of glucose metabolism known as the Warburg effect.. Early-stage LUAD was initially thought to have limited glycolytic activity due to absence of low [18F] fluorodeoxyglucose (FDG) signal. However, we reported that early LUAD are in fact glycolytically active and sequester glucose using the sodium-glucose transporter (SGLTs), leading to the identification of a new position emission tomography tracer, methyl 4- [18F]FDG (Me4FDG) that is transported exclusively by SGLTs. FDG is transported exclusively by GLUTs and thus, could not be used to measure the SGLT-mediated glucose consumption of pre-malignant and early stage LUAD. Furthermore, as the tumor progress to more advanced disease we observed spatial heterogeneity in SGLT2 and GLUT1 expression. The molecular advantages of this switch have yet to be fully elucidated. Our proposed work will answer basic questions regarding the cellular glucose transport efficiency of SGLT2 compared to GLUT1. We hypothesize that under conditions of low glucose availability and in early stages where the cancer cells are in direct competition with tumor-infiltrating immune cells, SGLT2 will prove to be a more efficient cellular transporter compared with GLUT1. We will also for the first time, investigate the impact of SGLT2 expression in shaping the tumor-immune landscape. We hypothesize the early glucose deprivation and increased production of lactate, a metabolite produced by highly glycolytic tumors, promotes immunosuppressive phenotypes in the tumor microenvironment. Our investigation into the metabolic competition between cancer and tumor resident immune cells will provide meaningful insights into novel combination treatment strategies that repairs the metabolic dysregulation, stimulates anti-tumor immune response, and eradicates LUAD in its’ early stage.

项目概要 肺癌是全球癌症相关死亡的主要原因，也是两国第二大常见癌症 男女。非裔美国男性患肺癌的可能性比白种人高约 15% 同行。肺腺癌是吸烟者和从未吸烟者中最常见的肺癌类型 吸烟者，约占所有病例的 30%。肺癌的治疗正在朝着专门药物的方向发展 靶向参与致癌作用的异常途径。其中一个令人感兴趣的领域是代谢功能障碍， 特别是葡萄糖代谢的上调，称为 Warburg 效应。早期 LUAD 最初是 由于缺乏低 [18F] 氟脱氧葡萄糖 (FDG) 信号，被认为糖酵解活性有限。然而， 我们报道过，早期的 LUAD 实际上具有糖酵解活性，并利用钠-葡萄糖来螯合葡萄糖 转运蛋白（SGLT），导致鉴定出新的位置发射断层扫描示踪剂甲基 4- [18F]FDG (Me4FDG) 仅由 SGLT 运输。 FDG 完全由过剩运输 因此，不能用于测量癌前和早期阶段 SGLT 介导的葡萄糖消耗 卢阿德。此外，随着肿瘤进展为更晚期的疾病，我们观察到空间异质性 SGLT2 和 GLUT1 表达。这种开关的分子优势尚未完全阐明。 我们提出的工作将回答有关 SGLT2 细胞葡萄糖转运效率的基本问题 与 GLUT1 相比。我们假设，在低葡萄糖可用性的条件下和早期阶段， 癌细胞与肿瘤浸润免疫细胞直接竞争，SGLT2将被证明是一种更有效的方法。 与 GLUT1 相比，它是高效的细胞转运蛋白。我们还将首次调查 SGLT2 的影响 塑造肿瘤免疫景观的表达。我们假设早期葡萄糖剥夺和 乳酸（一种由高度糖酵解肿瘤产生的代谢物）的产生增加，促进免疫抑制 肿瘤微环境中的表型。我们对癌症之间代谢竞争的研究 肿瘤驻留免疫细胞将为新型联合治疗策略提供有意义的见解 修复代谢失调，刺激抗肿瘤免疫反应，并根除“LUAD” 早期。