EPEN-08. Single-cell transcriptome analysis defines a tumor-supportive microenvironment and tumor-stroma crosstalk in pediatric ependymoma and medulloblastoma. (3rd June 2022) - Federico, Aniello
Abstract: Brain tumors are the leading cause of disease-related death in childhood and strong efforts are required to develop innovative and efficient therapeutic strategies for patients with high-risk disease. Key critical factor of pediatric brain tumors is their molecular heterogeneity; one of the aspects that contributes to such heterogeneity is the intrinsic capacity of the tumor cells to organize, shape and exploit the surrounding brain tumor microenvironment (TME) to sustain tumor growth and malignant progression. TME was proved to play a crucial role in several malignancies, but in pediatric brain malignancies this has not been fully elucidated yet. Here, we aimed at characterizing the TME cell populations and their contributions in ependymoma and medulloblastoma, two of the most common pediatric brain tumor entities. Single-cell transcriptome analysis (n=65 ependymomas; n=39 medulloblastomas) of publicly available tumor datasets, as well as newly generated data of primary tumors and matching patient-derived tumor xenografts (PDX), showed an extensive heterogeneity of TME cell types with distinctive expression signatures. Amongst the identified TME populations, analysis revealed pro-inflammatory and proliferating myeloid cells, tumor-infiltrating lymphocytes, active regulatory T cells and vascular progenitor cells. Comparative analysis between primary and PDX tumors showed that tumor cells stimulated the host microenvironment, which in turn exhibited tumor-associated stromal signatures. Applying a deconvolution method, using our single cell data as reference, on a bulk tumor cohort including PFA ependymomas with different degree of immune infiltration, we observed an enrichment of polarized macrophages and microglia cells in tumor with high infiltration. Next, we identified TME markers involved in tumor-supportive functions, such as immune suppression (TIGIT, FOXP3, BCL2, CD19, ICAM2), pro-inflammatory stimuli (CCL3, CCL4, IL1B, GPNMB), extracellular matrix remodeling (COL4A1) and angiogenic processes (ANGPT2). TME markers with emerging role in ependymoma and medulloblastoma can be considered as possible targets for tailored and more effective anti-tumor therapeutic strategies.