INNV-32. SUPER-INDUCTION OF IMMUNOSUPPRESSIVE GLIOBLASTOMA EXTRACELLULAR VESICLES BY IFN-γ. (11th November 2019)

• Record Type: Journal Article
• Authors: Jung, Mi-Yeon; Himes, Benjamin; Cumba-Garcia, Luz; Parney, Ian
• Is Part Of: Neuro-oncology. Volume 21(2019)Supplement 6
• Page Start: vi137
• Page End: vi137
• Publication Date: 2019-11-11
• Subjects: Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/noz175.573
• Languages: English
• ISSNs: 1522-8517

Abstract

Abstract: Glioblastoma (GBM) is the most common and aggressive primary brain tumor. Median survival is 15 months despite surgery, radiation, and chemotherapy. Immunotherapy is promising but GBM-mediated immunosuppression remains a barrier. Recently, extracellular vesicles (EVs) have been implicated in GBM-mediated immunosuppression through expression of the immune checkpoint molecule PD-L1. Data from our group has suggested this is predominantly through induction of immunosuppressive monocytes including myeloid-derived suppressor cells (MDSCs) and non-classical monocytes (NCMs). PD-L1 expression is increased in most nucleated cells following IFN-γ exposure. We, therefore, sought to determine if IFN-γ exposure would result in super-induction of immunosuppressive GBM EVs. EVs were harvested in vitro from matched differentiated and stem-like human GBM cell lines +/- IFN-γ. IFN-γ exposure did not alter EV production or expression of common EV markers but increased PD-L1 expression in EVs from differentiated but not stem-like GBM cells. In keeping with our earlier findings, no direct inhibition of T cell proliferation by stem-like or differentiated GBM EVs was observed regardless of IFN-γ exposure or PD-L1 expression. In contrast, differentiated but not stem-like GBM cell EVs induced MDSC and NCM differentiation from normal monocytes. This was increased following IFN-γ exposure and was dependent upon PD-L1 expression. Monocytes exposed to differentiated but not stem-like GBM cell EVs inhibited T cell proliferation in a similar manner (increased with IFN-γ exposure, decreased with PD-L1 knockdown). Thus, IFN-γ exposure results in super-induction of immunosuppressive EVs from differentiated but not stem-like GBM cells that increase MDSC and NCM differentiation in normal monocytes and increase their ability to inhibit T cell proliferation. These effects are dependent upon PD-L1 up-regulation induced by IFN-γ. This may be an important mechanism GBMs utilize to suppress anti-tumor T cell responses that are typically accompanied by increased IFN-γ expression.