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

Abstract

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