TMIC-56. TUMOR CELL ARCHITECTURAL HETEROGENEITY AND SPATIAL INTERACTIONS WITH THE TUMOR IMMUNE MICROENVIRONMENT IN GBM

Abstract

Abstract INTRODUCTION Glioblastoma (GBM) contains cell populations with distinct metabolic requirements, with fast-cycling cells harnessing aerobic glycolysis, and treatment-resistant slow-cycling cells (SCCs) preferentially engaging lipid metabolism. The interaction between immune and tumor cells, and how their metabolic heterogeneity shapes the immune landscape in GBM has yet to be understood. Objectives: The primary objective of this project is to spatially and molecularly decode the GBM microenvironment heterogeneity with a specific focus on unraveling the metabolic links that underlie the interaction of SCCs with the immune compartment. METHODS Multiple murine glioma cell lines coupled with geospatial profiling were used to establish metabolic heterogeneity and communications, while various genetic and pharmacological approaches were applied to assess the effect of disrupting the metabolic interplay between SCCs and the immune system. RESULTS We determined that SCCs exhibit distinct metabolic dependencies, involving preferential lipid metabolism supported by enhanced fatty acid uptake. We also found that SCCs exhibit specific geospatial distribution and that tumor progression is regulated by their interactions with immune suppressive cells, which in turn work against tumor immune rejection by inhibiting T cell anti-tumor activity. The immune microenvironment shaped by SCCs is marked by specific metabolic features enhancing lipid exchange capacities that are exploited by SCCs to support their survival and functions. Importantly, disrupting lipid metabolic exchange sensitized tumors to chemotherapy. CONCLUSION Our results reveal that metabolic interactions between SCCs and tumor-associated immune suppressive cells within the GBM microenvironment play a critical role in the development of drug and immune resistant tumors. This study delineates these metabolic communications and assesses the potential therapeutic effect of disrupting these interactions to treat GBM. The insights generated from this project uncover fundamental principles of the emerging connections between the tumor microenvironment, cell metabolism, anti-tumor immunity, and associated therapeutic vulnerabilities.