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.

项目摘要 肺癌是全球与癌症相关死亡的主要原因，在两者中都是第二常见的癌症 男女。非洲裔美国男性患肺癌的可能性比高加索人高15％ 同行。肺腺癌是两种吸烟者中最常见的肺癌类型，从不 吸烟者，占所有病例的约30％。肺癌的治疗正在朝着专门的药物迈进 涉及癌变的目标异常途径。感兴趣的领域之一是代谢功能障碍， 特别是葡萄糖代谢的上调称为沃堡效应。 由于缺乏低[18F]氟脱氧葡萄糖（FDG）信号，因此被认为具有有限的糖酵解活性。然而， 我们报告说，早期LuAD实际上是糖酵解活性的，并使用钠葡萄糖隔离了葡萄糖 转运蛋白（SGLTS），导致鉴定出新的位置发射断层扫描示踪剂，甲基4- [18F] FDG（ME4FDG）由SGLTS专门运输。 FDG专门由Gluts运输和 因此，不能用来测量SGLT介导的葡萄糖消耗前的葡萄糖和早期阶段 卢德。此外，随着肿瘤发展到更晚期疾病，我们观察到了空间异质性 SGLT2和GLUT1表达。该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的细胞葡萄糖传输效率的基本问题 与glut1相比。我们假设在低葡萄糖可用性的条件下，在早期 癌细胞与肿瘤浸润的免疫细胞直接竞争，SGLT2将被证明是更多 与GLUT1相比，有效的细胞转运蛋白。我们也将首次研究SGLT2的影响 塑造肿瘤免疫景观时的表达。我们假设早期的葡萄糖剥夺和 增加的糖尿病的产生是一种由高糖酵解肿瘤产生的代谢产物，可促进免疫抑制作用 肿瘤微环境中的表型。我们对癌症代谢竞争的调查 肿瘤居民免疫核算将为新型组合治疗策略提供有意义的见解 这可以修复代谢失调，刺激抗肿瘤的免疫响应，而放射线群则在其' 早期。