Abstract 2342: Quinolinate promotes alternatively activated macrophage-induced immune tolerance in glioblastoma through the NMDA/PPARy signaling axis

Abstract

Abstract There has been considerable scientific effort dedicated to understanding the biologic consequence and therapeutic implications of aberrant tryptophan metabolism in brain tumors and neurodegenerative diseases. An overwhelming majority of this work has focused on the upstream metabolism of tryptophan, however, this has not resulted in clinical application. Using global metabolomic profiling of patient-derived brain tumors, we identify the downstream metabolism of tryptophan and accumulation of quinolinate (QA) as a metabolic node in glioblastoma and went on to demonstrate its critical role in promoting immune tolerance. QA acts as a “metabolic checkpoint” in glioblastoma by inducing NMDA receptor activation and Foxo1/PPARγ signaling, resulting in amplification of immune suppressive macrophages. Using a genetically-engineered mouse model designed to inhibit production of QA, we identify kynureninase as a promising therapeutic target to revert the potent immune suppressive microenvironment in glioblastoma. These findings offer the scientific community an opportunity to revisit the biologic consequence of this pathway as it relates to oncogenesis and neurodegenerative disease and a framework for developing new immune modulatory agents to further clinical gains in these otherwise incurable diseases. Citation Format: Pravin Kesarwani, Shiva Kant, Antony Prabhu, Katie L. Buelow, C. Ryan Miller, Prakash Chinnaiyan. Quinolinate promotes alternatively activated macrophage-induced immune tolerance in glioblastoma through the NMDA/PPARy signaling axis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2342.