Influence of glucose heterogeneity on the tumor immune landscape

项目摘要 肺癌是世界范围内与癌症相关的死亡的主要原因，在两种疾病中都是第二常见的癌症 男人和女人。非裔美国人患肺癌的可能性比白人高约15% 对口单位。肺腺癌是吸烟者和从不吸烟的人中最常见的肺癌类型。 吸烟者，约占所有病例的30%。肺癌的治疗正朝着特定的药物发展 靶向参与癌变的异常通路。其中一个令人感兴趣的领域是代谢障碍， 具体地说，就是被称为华宝效应的葡萄糖代谢上调。早期的LUAD最初是 由于缺乏低[18F]氟代脱氧葡萄糖(FDG)信号，被认为糖酵解活性有限。然而， 我们报道，早期的LUAD实际上是糖酵解活性的，并利用钠-葡萄糖隔离葡萄糖 转运蛋白(SGLTS)，从而鉴定了一种新的位置发射断层扫描示踪剂甲基4- [18F]仅由SGLT运输的FDG(Me4FDG)。FDG完全由Gluts和 因此，不能用来测量SGLT介导的癌前和早期的葡萄糖消耗。 路德。此外，随着肿瘤进展为更晚期的疾病，我们观察到 SGLT2和GLUT1的表达。这种开关的分子优势还没有完全阐明。 我们提出的工作将回答有关SGLT2细胞葡萄糖运输效率的基本问题 与GLUT1相比。我们假设，在葡萄糖供应不足的情况下，在早期阶段 癌细胞与肿瘤浸润性免疫细胞直接竞争，SGLT2将被证明是一种更 与GLUT1相比，高效的细胞转运蛋白。我们还将首次调查SGLT2的影响 在塑造肿瘤免疫格局中的表达。我们假设早期的葡萄糖缺乏和 乳酸是一种由高度糖酵解肿瘤产生的代谢物，其产生的增加促进了免疫抑制 肿瘤微环境中的表型。我们对癌症之间代谢竞争的研究 肿瘤常驻免疫细胞将为新的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，并根除其体内的LUAD 早期阶段。

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.