Fatty Acid Metabolic Regulation of Anti-Tumor Immunity Against Irradiated Glioblastoma

PROJECT SUMMARY Glioblastoma (GBM) is a devastating brain tumor disease with a median overall survival of approximately 15 months. GBM patients die because of the constant ability of GBM to acquire resistance mechanisms against anti-cancer therapies, therefore leading to an inevitable tumor recurrence. Radiation therapy (RT) is a pivotal modality for improving overall survival of GBM. However, GBM invariably recurs, which suggests that RT is eliciting or exacerbating mechanisms of resistance in GBM. Identifying and overcoming the contributing factors involved in GBM resistance is a major challenge in Radiation Oncology. GBM metabolism and its role in immune evasion emerges as a RT-induced resistance mechanism in GBM. Specifically, we have preliminary data indicating that irradiated GBM cells reprogram their metabolism towards the generation of fatty acids. Such metabolic reprogramming after RT is impairing the innate immune recognition and systemic anti-tumor immunity elicited by RT. More precisely, we have preliminary evidence that fatty acid synthesis is inhibiting nucleic acid sensing-dependent interferon type I (IFN-I) responses and is promoting immunosuppressive signals such as the programmed-death-1 (PD-1) and the programmed-death ligand 1 (PD-L1). As a consequence, cancer cell-intrinsic IFN-I will not be released in response to RT. This ultimately limits anti-tumor immune response against GBM by precluding infiltration effector T cells into the GBM microenvironment. We have recently demonstrated that cancer cell-intrinsic IFN-I response is an essential step to convey immunogenicity of an irradiated tumor. Consequently, by increasing energy supply, limiting innate immunity and increasing immunosuppression, RT-induced fatty acid synthesis is likely to be a major GBM resistance mechanism that not only impacts RT response of GBM but also provides means to evade immune recognition. In this application, we propose to test the novel and innovative hypothesis that fatty acid metabolism induced by RT controls immune escape and GBM survival. Successful completion of this proposal will define how fatty acid synthesis facilitates GBM immune evasion and provide pre-clinical evidence for fatty acid inhibitors as a novel approach to restore the immunogenicity of irradiated GBM.