TMET-10. FATTY ACID METABOLISM REGULATES IMMUNE REACTIVITY OF IRRADIATED GLIOBLASTOMA

Abstract Radiation therapy (RT) is the standard-of-care for glioblastoma (GBM) and only treatment inoperable brain tumors. In multiple cancer, RT stimulates anti-tumor immunity by at least activating cancer cell-intrinsic type I interferon (IFN-I) responses. However, GBM inevitably recur, suggesting that promotes immune evasion mechanisms. Altered fatty acid (FA) metabolism an emerging mechanism can account resistance escape of GBM. Therefore, we hypothesize induces a metabolic shift toward production FAs to foster immunosuppression Supporting this hypothesis, our data show upregulates expression synthase (FASN) activity desaturase 2 (FADS2) generate in murine models, GL261 CT2A. To determine whether FA was preventing RT-induced IFN-I, impaired synthesis inhibiting either FASN or FADS2 using genetic (CRISPR-Cas9) pharmacological inhibitors (FASNi FADS2i). As expected, protein quantification (ELISA) as well gene (RT-qPCR) revealed irradiated cells released greater levels IFN-beta 24hrs post RT; effect more pronounced when were blocked. Reinforcing role regulating activation, situ immunofluorescence intracranial tumors showed mice treated with FASNi improved recruitment CD8+ T into Along similar lines, flow cytometry digested increase infiltration CD11c+ CD103+ dendritic activated CD86+ CD11b+ blocked FADS2i. Altogether, suggest represents IFN-I promoting immunological Targeting promising strategy promote sensitize immunotherapies.