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Abstract
Purpose: Immune checkpoint inhibitors designed to revert tumor-induced immunosuppression have emerged as potent anticancer therapies. Tryptophan metabolism represents an immune checkpoint, and targeting this pathway's rate-limiting enzyme IDO1 is actively being investigated clinically. Here, we studied the intermediary metabolism of tryptophan metabolism in glioblastoma and evaluated the activity of the IDO1 inhibitor GDC-0919, both alone and in combination with radiation (RT).Experimental Design: LC/GC-MS and expression profiling was performed for metabolomic and genomic analyses of patient-derived glioma. Immunocompetent mice were injected orthotopically with genetically engineered murine glioma cells and treated with GDC-0919 alone or combined with RT. Flow cytometry was performed on isolated tumors to determine immune consequences of individual treatments.Results: Integrated cross-platform analyses coupling global metabolomic and gene expression profiling identified aberrant tryptophan metabolism as a metabolic node specific to the mesenchymal and classical subtypes of glioblastoma. GDC-0919 demonstrated potent inhibition of this node and effectively crossed the blood-brain barrier. Although GDC-0919 as a single agent did not demonstrate antitumor activity, it had a strong potential for enhancing RT response in glioblastoma, which was further augmented with a hypofractionated regimen. RT response in glioblastoma involves immune stimulation, reflected by increases in activated and cytotoxic T cells, which was balanced by immune checkpoint reactivation, reflected by an increase in IDO1 expression and regulatory T cells (Treg). GDC-0919 mitigated RT-induced Tregs and enhanced T-cell activation.Conclusions: Tryptophan metabolism represents a metabolic node in glioblastoma, and combining RT with IDO1 inhibition enhances therapeutic response by mitigating RT-induced immunosuppression.

Author information

Kesarwani P1, Prabhu A1, Kant S1, Kumar P2, Graham SF2, Buelow KL1, Wilson GD1, Miller CR3, Chinnaiyan P4,5.
1
Department of Radiation Oncology, Beaumont Health, Royal Oak, Michigan.
2
Metabolomics and Obstetrics/Gynecology, Beaumont Research Institute, Beaumont Health, Royal Oak, Michigan.
3
Department of Pathology & Laboratory Medicine, Neurology, & Pharmacology, Lineberger Comprehensive Cancer Center and Neurosciences Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
4
Department of Radiation Oncology, Beaumont Health, Royal Oak, Michigan. prakash.chinnaiyan@beaumont.edu.
5
Oakland University William Beaumont School of Medicine, Royal Oak, Michigan.