Metabolic Reprogramming of Myeloid Cells via Heme Oxygenase Pathway in the Immunosuppressive Glioblastoma Microenvironment - Glioblastoma (GBM) is the most lethal primary brain tumor with a mean survival of only 12-15 months even with maximal treatment, a grim statistic that has remained relatively unchanged for decades. Despite efforts to advance treatment, GBM remains one of the most difficult cancers to combat. Although immunotherapy has shown promise in treating many other cancers such as lung cancer and melanoma, it has not yet led to increased survival benefits for GBM patients in clinical trials. Exploring strategies to overcome immunosuppression in GBM is paramount to making strides in GBM therapeutics. One way GBM creates a highly immunosuppressive environment is through the metabolic reprogramming of immune cells. Cancer cells preferentially utilize aerobic glycolysis (the Warburg effect). Recent studies suggest that immune cells in the tumor microenvironment (TME) may undergo a similar metabolic adaptation. One of the key metabolic pathways implicated in the immune- regulation of many cancers is the heme oxygenase-1 (HMOX-1) pathway. HMOX-1 is known to be upregulated in multiple cancers including GBM, and according to our transcriptomic data, its high expression is particularly prominent in pro-tumor myeloid cell populations, such as myeloid-derived suppressor cells (MDSCs). HMOX-1 overexpression in GBM has been associated with poor survival, while inhibition of HMOX-1 has been shown to downregulate immunosuppressive metabolic pathways involving L-arginine and L-tryptophan catabolism. However, our understanding of how HMOX-1 alters immune cell energy pathways to modulate immunosuppression remains limited. The goal of this project is to explore how redirecting MDSCs towards oxidative phosphorylation and away from glycolysis impacts their viability and immunosuppressive functions through the following specific aims: (1) determine the relationship between glycolytic shunting and survival of HMOX+ MDSCs in the GBM TME, (2) assess the effect of inhibiting HMOX-1 and reversing glycolytic shunting on the immunosuppressive behavior of MDSCs. Our central hypothesis is that the overexpression of HMOX-1 in MDSCs drives the adoption of a cancer-like glycolytic pathway that promotes their survival in the GBM TME and that restoring oxidative phosphorylation via HMOX-1 inhibition can reverse their immunosuppressive effects. We expect HMOX-1 overexpression in MDSCs to drive glycolytic shunting and reversal of this glycolytic pathway via the inhibition of HMOX-1 in MDSCs to reduce their immunosuppressive effect either by impacting MDSC viability or rehabilitating their anti-tumor characteristics, as measured by improved antigen presentation and increased anti-tumoral cytokine release, leading to enhanced T cell activation. Successful execution of this project will have a significant, measurable impact as we highlight the major role of HMOX-1 in the metabolic switch that enables the propagation of immunosuppressive myeloid cell populations in the GBM TME and demonstrate its potential as a therapeutic target. Through this F32 fellowship, Dr. Kim will receive invaluable training necessary for her growth as a physician-scientist.
