Tryptophan metabolism contributes to radiation-induced immune checkpoint reactivation in glioblastoma
Clinical Cancer Research
© 2018 American Association for Cancer Research. 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 RTinduced immunosuppression.
Kesarwani, Pravin; Prabhu, Antony; Kant, Shiva; Kumar, Praveen; Graham, Stewart F.; Buelow, Katie L.; Wilson, George D.; Miller, C. Ryan; and Chinnaiyan, Prakash, "Tryptophan metabolism contributes to radiation-induced immune checkpoint reactivation in glioblastoma" (2018). Articles. 50.