Project Grant R01NS129744

QUINOLINATE-INDUCED IMMUNE SUPPRESSION IN GLIOBLASTOMA - ABSTRACT RECENT ADVANCEMENTS USING IMMUNE CHECKPOINT INHIBITORS DESIGNED TO TARGET TUMOR-MEDIATED IMMUNE TOLERANCE HAVE REVOLUTIONIZED CANCER THERAPY. UNFORTUNATELY, THESE CLINICAL SUCCESSES HAVE NOT TRANSLATED TO GLIOBLASTOMA (GBM), WHICH CONTINUES TO BE AN INVARIABLY FATAL MALIGNANCY WITH LIMITED TREATMENT OPTIONS. ONE OF THE LEADING THOUGHTS IN THE FIELD EXPLAINING THIS LACK OF CLINICAL BENEFIT IN GBM IS THAT THESE AGENTS ARE ACTING UPON THE WRONG TARGET. TUMOR-ASSOCIATED MACROPHAGES (TAMS) APPEAR TO REPRESENT THE PRIMARY IMMUNE CELLS CONTRIBUTING TOWARDS THE IMMUNE SUPPRESSIVE MICROENVIRONMENT IN GBM, VASTLY OUTNUMBERING T CELL INFILTRATION. HENCE, THERE IS CONSIDERABLE INTEREST IN DEVELOPING THERAPEUTIC STRATEGIES DESIGNED TO TARGET M2 TAMS OR REVERT THEIR POLARIZATION TO ENHANCE ANTITUMOR IMMUNITY. WE DISCOVERED THE ACCUMULATION OF QUINOLINATE (QA), A DOWNSTREAM INTERMEDIATE OF TRYPTOPHAN METABOLISM, AS A PREVIOUSLY UNDESCRIBED METABOLIC NODE IN GBM. THROUGH A SERIES OF INVESTIGATIONS, WE WENT ON TO DEMONSTRATE THE POTENT ABILITY OF QA TO SCULPT THE GBM IMMUNE LANDSCAPE BY POLARIZING MACROPHAGES TOWARDS THE IMMUNE SUPPRESSIVE M2 PHENOTYPE. POTENT ANTI-TUMOR ACTIVITY WAS OBSERVED WHEN TESTED IN GBM LINES GROWN INTRACRANIALLY, SUPPORTING THE THERAPEUTIC POTENTIAL OF TARGETING QA METABOLISM IN GBM. IN THIS PROPOSAL, WE NOW SEEK TO DEFINE MECHANISMS CONTRIBUTING TOWARDS QA-MEDIATED MACROPHAGE POLARIZATION (AIM 1), EXTEND STUDIES EVALUATING THE IMMUNOLOGIC/METABOLIC CONSEQUENCE OF TARGETING QA IN GBM (AIM 2), AND IDENTIFY RATIONAL COMBINATORIAL STRATEGIES DESIGNED TO EXPLOIT INHIBITION OF QA-INDUCED IMMUNE SUPPRESSION (AIM 3). IF SUCCESSFUL, THESE RESULTS WOULD OFFER A PREVIOUSLY UNRECOGNIZED WINDOW INTO THE COMPLEX METABOLIC INTERPLAY BETWEEN TUMOR AND IMMUNE CELLS IN THE GBM MICROENVIRONMENT, ITS FUNCTIONAL CONSEQUENCE ON IMMUNE SUPPRESSION, AND FRAMEWORK FOR THE IDENTIFICATION OF NOVEL THERAPEUTIC STRATEGIES IN THIS AGGRESSIVE MALIGNANCY WITH LIMITED TREATMENT OPTIONS.