OS11.7.A DELETION OF MONOCARBOXYLATE TRANSPORTER 1 IN MYELOID CELLS FAVOURS GLIOBLASTOMA DEVELOPMENT

Abstract BACKGROUND Glioblastoma (GB) is the most aggressive tumor of the central nervous system, with a median survival of less than 15 months after diagnosis. The standard of care consists in surgical resection followed by radio-chemotherapy. However, patients are subject to a high rate of tumor recurrence, explained by an enriched immune environment in myeloid cells, which represent up to 70% of tumor weight and have immunosuppressive and/or pro-tumoral properties. GB possesses highly invasive properties due to its hypoxic and acidic core. Acidity is mainly mediated by the released of protons with lactate coming from tumor cells. Lactate is known to be responsible for immuno-metabolic modifications of immune cells in other cancers. Altogether, immunosuppressive/pro-tumoral macrophages abundancy and lactate concentration may impact tumor development and patient’s outcome. However, the specific effects of lactate on the phenotypes and functions of myeloid cells in the GB tumor microenvironment is poorly understood. MATERIAL AND METHODS The brain’s immune environment is unique. To study effects of microglia, which are resident macrophages, and of macrophages, that infiltrated brain from the bloodstream, on GB development, mouse models deficient for the lactate transporter MonoCarboxylate Transporter 1 (MCT1) either in all myeloid cells (Mct1Δmye), or specifically depleted in microglia (Mct1ΔMG) as well as constitutively depleted in lactate signalling, for the receptors GPR81 or GPR132 have been generated in both sexes. RESULTS AND CONCLUSION Disruption of lactate signalling through Gpr81 deficiency did not affect GB growth in our model. In contrast, male Gpr132 knockout mice (Gpr132-/-) displayed significantly reduced tumor volume compared to WT. ScRNA seq showed that Gpr132 is highly expressed in immune cells. Surprisingly, flow cytometry analysis of the immune infiltrate revealed no significant difference in in bone-marrow-derived or microglia tumor-associated macrophages (BM-TAMs vs MG-TAMs), suggesting that lactate signalling through Gpr132 regulate tumor growth with minimal influence of immune system. ScRNAseq also showed that Mct1 is expressed in myeloid cells. Then, we investigated the role of Mct1 by using the myeloid-specific deficiency model (Mct1Δmye). In vivo experiments revealed a sex-dependent effect in Mct1Δmye mice compared to control, with males exhibiting significantly larger tumors than WT mice. Interestingly, in vitro respiration assays demonstrated that Mct1Δmye BMDMs have a lower respiration rate on lactate compared to controls. For Mct1Δmye, a detailed analysis of the metabolic differences between WT and Mct1Δmye BMDMs is currently under investigation. These findings suggest intriguing regulatory roles of lactate signalling and transport on GB tumor growth, with a potential sex-specific responses mediated by Mct1 and lactate flux.