Glucose and Glutamine in the Tumor Microenvironment and CD8 T Cell Function
Madden, Matthew Zachary
Metabolism determines cell function and fate across tissues and disease states. Proliferative cells upregulate anabolic metabolism to support cell growth, division, and other activities. Glucose and glutamine are critical nutrients for both cancer cells and activated immune cells, and 18F-deoxyglucose positron emission tomography (FDG PET) imaging is used clinically to monitor tumors in patients. Using 18F tracers, we establish that in vivo glucose uptake in the tumor microenvironment is highest in myeloid cells, not cancer cells as has been previously assumed. In contrast, cancer cells uptake relatively more glutamine and fatty acids. Transcriptional programs and mTORC1 signaling support cell type-specific nutrient uptake. Our results support a model of cell-programmed nutrient partitioning, not nutrient competition, in the tumor microenvironment and may have ramifications for clinical FDG and 18F-glutamine PET imaging. Cytotoxic CD8 T cells effect anti-tumor immunity by eliminating cancer cells, and glutamine promotes CD8 differentiation. Here we show that different glutamine-targeting strategies during initial CD8 cell activation produce distinct effects relevant for anti-tumor function. Glutaminase (GLS)-specific inhibition causes CD8 cells to utilize more glycolysis but has less profound effects than pan-glutamine inhibition or glutamine deprivation. Pan-glutamine inhibition during initial activation reduces in vivo persistence and impairs elimination of tumors, whereas glutamine deprivation worsens the memory capacity of CD8 cells. Differential CD8 cell fates are associated with transcriptional, metabolic, and epigenetic changes. These data inform the development of glutamine-targeting therapeutics for oncology and immunomodulation. Overall, this dissertation demonstrates the importance of interrogating specific cell types and metabolic interventions in the context of the complex tumor microenvironment and cancer therapies.