P02.12.A DISTINCT MODULATION OF METABOLISM AND GLIOMA-ASSOCIATED MICROENVIRONMENT BY DEXAMETHASONE AND BEVACIZUMAB

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Abstract BACKGROUND Glioblastomas are aggressive primary tumors of the central nervous system with limited registered therapeutic options. Peritumoral vasogenic or treatment-associated edema —commonly observed after radiation or immunotherapy—poses a significant clinical burden in glioblastoma patients. Dexamethasone (DEXA), a synthetic glucocorticoid, is commonly used in clinical practice in these situations, though its immunosuppressive effects may counteract immunotherapeutic strategies. Bevacizumab (BEV), an anti-VEGF antibody, is increasingly utilized in clinical practice to address therapy-induced edema. In this study, we investigated the differential effects of DEXA and BEV on tumor metabolism and the glioma-associated microenvironment in experimental models. MATERIAL AND METHODS We performed ex vivo proton nuclear magnetic resonance (1H-NMR) spectroscopy-based metabolomics on glioma long-term cell lines upon treatment with DEXA or BEV to assess metabolic changes. Cytokine-release profiles were analyzed by ELISA. Microenvironmental modulation was further examined using co-culture systems and a syngeneic orthotopic glioma mouse model with immune profiling by flow cytometry and immunohistochemistry. RESULTS Comparison of DEXA and BEV treated glioma long-term cell lines revealed changes in abundance of distinct metabolites involved in energy and amino acid metabolism (e.g. lactate, alanine). DEXA and BEV elicited distinct cytokine-release profiles in glioma long-term cell lines. In vivo, BEV treatment led to a reduced presence of regulatory T cells (CD4⁺FOXP3⁺) and an increased proportion of activated T cells (CD4⁺GzmB⁺) in the tumor microenvironment as compared to DEXA. CONCLUSION DEXA and BEV exert distinct effects on glioma metabolism and immune microenvironmental composition. These molecular insights could inform clinical strategies for managing treatment-associated cerebral edema in clinical trials investigating immunotherapeutic approaches.

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