Intrinsic Interferon Signaling Regulates the Cell Death and Mesenchymal Phenotype of Glioblastoma Stem Cells

SIMPLE SUMMARY: Interferon signaling is mostly studied in the context of immune cells. However, its role in glioma cancer cells is unclear. This study aimed to investigate the role of cancer-cell-intrinsic IFN signaling in tumorigenesis in glioblastoma (GBM). We found that GSCs and GBM tumors exhibited differential cell-intrinsic type I and type II IFN signaling, and the high IFN/STAT1 signaling was associated with mesenchymal phenotype and poor survival in glioma patients. IFN-β exposure induced cell death in GSCs with intrinsically high IFN/STAT1 signaling, and this effect was abolished by inhibition of IFN/STAT1 signaling. A subset of GBM patients with high IFN/STAT1 may benefit from the IFN-β therapy. ABSTRACT: Interferon (IFN) signaling contributes to stemness, cell proliferation, cell death, and cytokine signaling in cancer and immune cells; however, the role of IFN signaling in glioblastoma (GBM) and GBM stem-like cells (GSCs) is unclear. Here, we investigated the role of cancer-cell-intrinsic IFN signaling in tumorigenesis in GBM. We report here that GSCs and GBM tumors exhibited differential cell-intrinsic type I and type II IFN signaling, and high IFN/STAT1 signaling was associated with mesenchymal phenotype and poor survival outcomes. In addition, chronic inhibition of IFN/STAT1 signaling decreased cell proliferation and mesenchymal signatures in GSCs with intrinsically high IFN/STAT1 signaling. IFN-β exposure induced apoptosis in GSCs with intrinsically high IFN/STAT1 signaling, and this effect was abolished by the pharmacological inhibitor ruxolitinib and STAT1 knockdown. We provide evidence for targeting IFN signaling in a specific sub-group of GBM patients. IFN-β may be a promising candidate for adjuvant GBM therapy.