TMET-11. QUINOLINATE PROMOTES ALTERNATIVELY ACTIVATED MACROPHAGE-INDUCED IMMUNE TOLERANCE IN GLIOBLASTOMA THROUGH THE NMDA/PPARG SIGNALING AXIS

Abstract There has been considerable interest in understanding the biological consequence and therapeutic implications of aberrant tryptophan metabolism brain tumors neurodegenerative diseases. An overwhelming majority this work focused on first-step (kynurenine); however, yet to result clinical application. Using global metabolomic profiling >100 patient-derived tumors, we identified a 64-fold accumulation quinolinate (QA), downstream metabolic intermediate pathway, glioblastoma when compared low-grade glioma. As several metabolites pathway have implicated immune modulation, sought determine impact QA microenvironment. We capacity strongly skew macrophage polarization towards “pro-tumorigenic” M2-phenotype with suppressive properties, which recent studies suggest play dominant role microenvironment glioblastoma. Intriguingly, conferred an “M2-like” phenotype M1 macrophages microglia, attenuating their phagocytosis efficiency. went systematically delineate novel mechanism through QA-induced NMDA receptor activation Foxo1/PPARg signaling. then determined that tumor cells host macrophages/microglia concert complete both upstream tryptophan, respectively, resulting QA. discovered very strong positive feedback loop involving expression kynureninase (KYNU) macrophages, enzyme involved production, making lead candidate for targeting pathway. represents target agents designed inhibit are not commercially available, generated Kynu-/- knockout mouse model. consistent vitro data, grown mice had ~50% reduction M2 increased activation, decreased growth, improved overall survival two orthotopic models, supporting potential