Quinolinate promotes macrophage-induced immune tolerance in glioblastoma through the NMDAR/PPARγ signaling axis

• Published in: Nature communications Vol. 14; no. 1; pp. 1459 - 16
• Main Authors: Kesarwani, Pravin, Kant, Shiva, Zhao, Yi, Prabhu, Antony, Buelow, Katie L., Miller, C. Ryan, Chinnaiyan, Prakash
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 16.03.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/105; 13/106; 13/31; 13/51; 13/89; 38; 49/15; 59; 631/67/1922; 631/67/2327; 631/67/580; 64; 64/60; Accumulation; Animals; Biological Products - metabolism; Brain; Brain cancer; Brain Neoplasms - pathology; Brain tumors; Cell activation; FOXO1 protein; Genetic engineering; Glioblastoma; Glioblastoma - genetics; Glutamate receptors; Glutamic acid receptors (ionotropic); Humanities and Social Sciences; Immune Tolerance; Immunological tolerance; Macrophages; Macrophages - metabolism; Metabolism; Metabolomics; Mice; Microenvironments; multidisciplinary; N-Methyl-D-aspartic acid receptors; Neurodegenerative diseases; Neurodegenerative Diseases - metabolism; Peroxisome proliferator-activated receptors; Phenotypes; PPAR gamma - metabolism; Quinolinic Acid - metabolism; Receptor mechanisms; Receptors, N-Methyl-D-Aspartate - metabolism; Science; Science (multidisciplinary); Signaling; Therapeutic targets; Tryptophan; Tryptophan - metabolism; Tumor Microenvironment; Tumorigenesis; Tumors; Upstream
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-37170-z

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. A majority of this work has focused on the upstream metabolism of tryptophan; however, this has resulted in limited 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 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 in macrophages, resulting in a tumor supportive phenotype. 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 an opportunity to revisit the biologic consequence of this pathway as it relates to oncogenesis and neurodegenerative disease and a framework for developing immune modulatory agents to further clinical gains in these otherwise incurable diseases. The upstream metabolism of tryptophan has been described as a metabolic node in glioblastoma. Here the authors show that the downstream metabolism of tryptophan, resulting in the accumulation of quinolinate in glioblastoma, contributes to pro-tumorigenic immune suppressive activation of macrophages.