TMET-07. Fructose metabolism is a unique feature of immunosuppressive myeloid cells in brain tumors

Abstract Gliomas are devastating brain tumors in adults and children. The metabolic milieu of the brain shapes the immune microenvironment, which is dominated by tumor-associated myeloid cells (TAMs; both blood-derived macrophages and brain-resident microglia). The brain is unique, with >25-fold higher concentration of fructose in the cerebrospinal fluid relative to the plasma. However, whether fructose influences glioma growth is unclear. Therefore, our goal was to delineate the role of fructose in gliomas. Quantitative flow cytometry showed that TAMs from murine gliomas expressed high levels of the fructose transporter SLC2A5 (>150,000 molecules/cell), unlike tumor cells, astrocytes, T cells, or endothelial cells (<2,000). Human TAMs generated by exposing human microglia to conditioned media from patient-derived glioma cells also upregulated SLC2A5, confirming clinical relevance. Stable isotope tracing demonstrated lactate production from 13C-fructose in murine and human TAMs, but not tumor or other non-neoplastic cells. Notably, these findings were oncogene-independent and conserved across adult (glioblastoma, IDH mutant) and pediatric (H3K27M, BRAFV600E) gliomas. Strikingly, genetic or pharmacological ablation of SLC2A5 in murine and human TAMs abrogated lactate production and reduced T cell suppression in vivo. Mechanistically, lactate activated immunosuppressive gene expression (HMOX1, LGALS3, TGFB1, CD274, HAVCR2) in TAMs via promoter histone H3K18 lactylation. Next, we questioned whether deuterium metabolic imaging, which is a clinical-stage method of tracing metabolism, could be used for imaging immunosuppressive TAMs. Human and murine TAMs polarized to an immunosuppressive phenotype produced lactate from [6,6-2H]-fructose, unlike those polarized to a proinflammatory state. Importantly, depleting TAMs using the CSF1R inhibitor sotuletinib or rewiring them to a proinflammatory state using an anti-TIM3 antibody resulted in the loss of lactate production in vivo, confirming that [6,6-2H]-fructose is a unique tracer of immunosuppressive TAMs in gliomas. Collectively, we leverage a mechanistic understanding of fructose metabolism for non-invasive metabolic imaging of TAM-driven immunosuppression in vivo.