Deciphering Cell Specific Metabolic Programs in the Tumor Microenvironment

Abstract

The tumor microenvironment (TME) is rich with proliferating tumor cells and infiltrating immune cells. In these niches, glucose, glutamine, and fatty acids are consumed. However, it was previously underappreciated to what extent these nutrients were metabolized by these different cell types. Therefore, we developed a new methodology to track the fate of radioactive glucose, and glutamine as well as florescent fatty acids into distinct cell populations in the TME in vivo. Using this technique, I observed glucose as a myeloid preferred substrate while tumor cells consumed the most per cell glutamine and fatty acids. These metabolic programs were dictated by unique transcriptional programs in each cell subset. Further examination of the myeloid glycolytic transcriptional program uncovered hexokinase 3 (HK3) as a myeloid-specific glycolytic gene. Through cytokine stimulation of macrophages, HK3 was found to be an interferon-gamma (IFNγ) stimulated gene. Given the prognostic role of IFNγ in human tumors, I then investigated the role of HK3 in kidney cancer. Surprisingly, this overlooked metabolic gene imparts a poor prognosis in untreated patients but predicts response to combination immunotherapy. In total, this work demonstrates that individual cell populations have metabolic preferences. These distinct metabolic programs can potentially be used as biomarkers given the cell type-specific expression as well as regulatory elements of certain metabolic genes.