IMMU-22. BLOCKADE OF CD47 RESULTS IN METABOLIC REPROGRAMMING TO ENHANCE IMMUNE CELL-MEDIATED CYTOTOXICITY OF GLIOBLASTOMA

Abstract

Abstract Glioblastoma (GBM) is the most aggressive and malignant brain tumor. There is growing interest in using immunotherapy to treat GBM, however, clinical trials with immune checkpoints have shown little efficacy, likely due to significant GBM-associated systemic and intra-tumoral immunosuppression. The expression of the transmembrane protein CD47 contributes significantly to immunosuppression limiting innate and adaptive anti-tumor responses. Our new data shows that patient biopsies showed strong immunoreactivity to CD47 in GBM compared to normal adjacent tissue. Furthermore, high CD47 expression in GBM patients resulted in poor survival, indicating that CD47 may be a potential target for GBM treatment. Beyond the “don’t eat me signal”, CD47 facilitates its intracellular signaling through PLIC1 and it still unknown how CD47-related can influence metabolic reprogramming in the tumor microenvironment. Previous studies that upregulated fatty acid oxidation (FAO) provide GBM cells with metabolic plasticity to accommodate its dynamic nutrient microenvironment. Respirometry data revealed that blocking CD47 in murine cell line (CT2A) reduces mitochondrial function and ATP production by over 40-50% respectively (p*< 0.02). The reduction in mitochondrial respiration is linked to an over 50% reduction in FAO (*p< 0.004). This was associated with significant decreases in CPT1a, FASN, ATGL, and CD36 indicating a reduction in FA metabolism mediators. On the other hand, blocking CD47 on murine microglia (SIMA9), showed an opposite result from cancer cells, with increasing mitochondrial respiration and FAO. Initial shows differential responses may be due to the engagement of PLIC1 to CD47. Furthermore, blocking CD47 on microglia increased three-fold of the immune cell-mediated GBM cell cytotoxicity (*p< 0.005), suggesting that metabolic reprogramming associated with CD47 blockade could result in the improvement of immune adaptive responses in the GBM microenvironment. Taken together, our data indicated that CD47 blockade may be a prospective treatment to reduce GBM metabolic plasticity and increase microglia-mediated GBM killing.