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Immune checkpoint blockade has re-stimulated the interest of immunotherapeutic strategies for glioblastoma (GBM). However, PD-1 blockade in recurrent GBM patients failed to meet the primary endpoint of superior survival (NCT02017717) highlighting the need to identify mechanisms of GBM immune evasion. One possibility is the metabolic landscape that cancer cells generate to promote survival and prevent immune responses. Radiation therapy (RT), a standard of care for GBM, is well-documented to reprogram the metabolism of the tumor microenvironment (TME). Therefore, we hypothesize that RT generates a metabolic shift in the TME to support GBM survival and immunosuppression. To address this question, we first defined RT-induced metabolic changes by Seahorse assay. We observed that mitochondrial respiration and ATP production were significantly increased in 10 gray (Gy)-irradiated GL261 cells after 24hr. Metabolomic profiling of 10Gy-irradiated GL261 cells showed a strong increase in metabolic pathways related to nucleotide, amino acids and lipid metabolism. We next ask whether RT was modulating the fatty acid synthase (FASN), a key lipogenic enzyme. Western blot analysis indicated upregulation of FASN expression in irradiated GL261 cells. Interestingly, flow cytometry of orthotopically implanted GL261 tumors not only confirmed FASN upregulation in cancer cells in vivo, but also revealed a marked FASN expression in tissue-resident microglia after 10Gy focal irradiation. Moreover, flow cytometry analysis showed increased expression of the immunosuppressive markers PD-L1 and CSF-1R in macrophages co-cultured with irradiated GL261. Finally, targeting FASN using shRNA or pharmacological inhibition, significantly reduced the proliferation of GL261 cells. Altogether, our data indicate that RT is rewiring the energy supply of GBM to presumably foster its growth and immunosuppression of the TME by promoting lipid biosynthesis. While much work remains to be done to confirm this hypothesis, our data propose FASN as a novel therapeutic target to overcome RT resistance and reduce immunosuppression in GBM.

TAMI-27. RADIATION THERAPY REPROGRAMS THE TUMOR METABOLISM TO PROMOTE SURVIVAL AND IMMUNOSUPPRESSION IN GLIOBLASTOMA