TMET-10. FATTY ACID METABOLISM REGULATES IMMUNE REACTIVITY OF IRRADIATED GLIOBLASTOMA. (14th November 2022)

• Record Type: Journal Article
• Authors: De Martino, Mara; Daviaud, Camille; Laiakis, Evagelia; Vanpouille-Box, Claire
• Is Part Of: Neuro-oncology. Volume 24(2022)Supplement 7
• Page Start: vii263
• Page End: vii263
• Publication Date: 2022-11-14
• Subjects: Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/noac209.1015
• Languages: English
• ISSNs: 1522-8517

Abstract

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