The impact of immunometabolism in cancer and inflammatory diseases

1. The role of the hexosamine biosynthetic pathway in anti-tumor immunity and autoimmunity. It is increasingly appreciated that both tumor cells and immune effector cells (e.g. T cells and macrophages) undergo significant cellular metabolic adaptations to promote energetically costly proliferation and effector functions. The prime example of such metabolic adaptation is the Warburg effect, in which tumor and immune cells preferentially switch their metabolism to aerobic glycolysis. Additional metabolic adaptations include augmented glutamine anaplerosis and alterations to the TCA cycle and electron transport chain, to name a few. The hexosamine biosynthetic pathway (HBP), which is an off branch of glysolysis and glutaminolysis has recently emerged as an important regulator of cancer and immunity. The endproduct of this pathway is protein glycosylation, in which UDP-GlcNAc is coupled to serine/threonine residues of target proteins by O-GlcNAc transferase (OGT). This aim include two separate projects in which we wish to explore the role of HBP in cancer and auto-immunity.

2. Impact of tumor acidosis on microglia phenotype and function in glioblastoma. A critical outcome of tumor cells metabolic shift to glycolysis is the significant release of lactate in the tumor microenvironment. We hypothesize that lactate uptake or signaling in immune cells of the tumor microenvironment suppresses their anti-tumor activity, as a tumor immune escape strategy. We will test this hypothesis in GBM and explore the specific impact of lactate on microglia and infiltrating TAMs.