Influence of glucose heterogeneity on the tumor immune landscape

项目总结

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.