Abstract
Diffuse midline glioma (DMG) represents a highly aggressive pediatric brain tumor with no chance of survival. Treatment options are urgently needed, and efforts have been put towards developing T-cell immunotherapy. However, this should consider DMG’s unique tumor microenvironment (TME), both in terms of anatomical location and developmental stage. To gain knowledge on this unique tumor niche, we implemented an immuno-competent, syngeneic mouse model based on in-utero electroporation (IUE) of the key driver mutations to induce tumor formation at an embryonic stage. We characterized DMG’s spatial and molecular landscape by combining snRNAseq, spatial transcriptomics, and state-of-the-art imaging. 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 novel signaling 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.