P02.05.a dissecting the diffuse midline glioma tumour microenvironment communications using multi-omics approaches

Abstract BACKGROUND Diffuse midline glioma (DMG) represents a highly aggressive pediatric brain tumour with no chance of survival. Treatment options are urgently needed, and efforts have been put towards the development of T cell immunotherapy. However, this should consider the unique tumour microenvironment (TME) of DMG, both in terms of anatomical location and developmental stage. MATERIAL AND METHODS To gain knowledge on this unique tumour niche, we implemented an immuno-competent, syngeneic mouse model based on in-utero electroporation (IUE) of the key driver-mutations to induce tumour formation at embryonic stage. By combining snRNAseq, Spatial Transcriptomics and state-of-the-art imaging, we characterized the spatial and molecular landscape of DMG. RESULTS AND CONCLUSION We observed a high intratumoral heterogeneity with spatially restricted cell populations. Importantly, their molecular profiles correlate with patient data, illustrating the clinical relevance of the IUE model. Analysis of cell-cell communications in the TME revealed a novel signalling between DMG and immunosuppressive myeloid cells, that could impact T-cell response. Using an advanced patient-derived DMG organoid co-culture model with macrophages and engineered T-cells, we are currently investigating the role of this pathway on T-cells mediated killing of DMG organoids. Thus, this project fills a critical need to delineate and overcome the immune-suppressive environment in DMG and potentiate T cell targeting.