DDRE-26. THE IMMUNO-METABOLIC ENZYME FASN PREVENTS CANCER-CELL INTRINSIC TYPE I INTERFERON RESPONSES IN GLIOBLASTOMA

Abstract

Glioblastoma (GBM) is a devastating primary brain cancer with a median survival of 11–15 months. Radiation therapy (RT), the standard of care for GBM, can generate type I interferon responses (IFN-I) to jumpstart antitumor immunity. However, these effects are sometimes mitigated by inhibitory mechanisms that are exacerbated by RT. RT can modify GBM metabolism to promote de novo lipogenesis via the fatty acid synthase (FASN). Because FASN was found to impair IFN-I in antiviral immunity, we hypothesize that FASN is preventing RT-induced IFN-I responses to promote GBM survival and evade immune recognition. We first defined RT-induced metabolic changes in the GL261 murine GBM model. We observed an increase in mitochondrial respiration, glycolysis and in lipid metabolism-related pathways in 10 gray (Gy) irradiated GL261 cells. Additionally, we found upregulation of FASN by western blot and lipid accumulation by BODIPY staining in 10 Gy-GL261 cells. RT-induced lipid accumulation was reverted when GL261 cells were incubated with a FASN inhibitor. Next, to ask whether FASN was impairing IFN-I, GL261 cells were engineered to express an inducible shRNA silencing FASN (GL261shFASN) or its non-silencing control (GL261shNS). As expected, irradiation of GL261shNS cells enhanced the secretion of IFN-beta and CXCL10. This effect was more pronounced when FASN was abrogated in GL261 independently from the presence of RT. Finally, GL261shNS and GL261shFASN cells were orthotopically implanted in mice and IFN-I signaling was blocked by anti-IFN-I receptor antibody (a-IFNAR). Mice bearing GL261shFASN tumors presented a median survival of 51 days vs. 35 days for GL261shNS tumors, a significant prolongation of mice survival that was completely abrogated with a-IFNAR treatment. Overall, our findings suggest that FASN-mediated lipogenesis prevents RT-induced cancer cell intrinsic IFN-I to promote GBM survival. Consequently, it is possible that FASN acts as an immuno-metabolic checkpoint capable to regulate the immune system upon metabolic cues generated by RT.