IMMU-19. QUINOLINATE-INDUCED IMMUNE SUPPRESSION IN GLIOBLASTOMA

Glioblastoma continues to be an invariably fatal malignancy with limited treatment options. We performed integrative cross-platform analyses coupling global metabolomic profiling with genomics in patient-derived tumors to provide insight into metabolic programs that may be driving the aggressive phenotype of this malignancy. A persistent theme that emerged was the interplay between metabolic remodeling and immune response. Most notable was a 64-fold accumulation of quinolinate, which represents a downstream intermediary of tryptophan metabolism, in glioblastoma, when compared to low-grade astrocytoma. We discovered a dynamic interaction between cells within the tumor microenvironment that contributes to the generation of quinolinate. Specifically, neither tumor cells nor immune cells demonstrated the capacity to completely metabolize tryptophan. Tumor cells were required to metabolize tryptophan to kynurenine, while only cells of monocyte lineage, including M1/M2 macrophages and microglial cells, demonstrated the capacity to generate quinolinate from tumor-generated kynurenine. We next sought to determine if the observed accumulation of quinolinate in glioblastoma had immune consequences. We discovered a novel role quinolinate plays in increasing (~50%) immunosuppressive M2 macrophage (CD45+CD11b+F4/80+ and CD206+) polarization and promoting a suppressive molecular phenotype (IL4Rα +). These findings were functionally recapitulated, with quinolinate-induced M2 macrophages demonstrating potent inhibition of CD8+T-cell proliferation. Intriguingly, quinolinate also skewed M1 polarization towards an “M2-like” phenotype both molecularly (CD45+CD11b+F4/80+CD206+) and functionally, by inhibiting CD8+T-cell proliferation and decreasing phagocytosis efficiency. Targeting quinolinate’s upstream enzyme kynurenine-3-monooxygenase (KMO) inhibited M2 polarization in vitro and deceased M2 macrophage levels in vivo by 60%. This was unique to KMO, as targeting tryptophan metabolism by inhibiting the more established, upstream target IDO1 did not influence M2 macrophage levels. As emerging studies suggest M2 macrophages play a central role in contributing towards the potent immunosuppressive microenvironment in glioblastoma, therapeutic strategies designed to target quinolinate metabolism may serve as a novel immuno-metabolic checkpoint with direct clinical implications in this malignancy.