Neoplastic and Immune single cell transcriptomics define subgroup-specific intra-tumoral heterogeneity of childhood medulloblastoma.

Medulloblastoma (MB) is a heterogeneous disease in which neoplastic cells and associated immune cells contribute to disease progression. To better understand cellular heterogeneity in MB we profile neoplastic and immune populations in childhood MB samples using single-cell RNA sequencing, immunohistochemistry and deconvolution of transcriptomic data. Neoplastic cells cluster primarily according to individual sample of origin which is in part due to the effect of chromosomal copy number gains and losses. Harmony alignment reveals novel MB subgroup/subtype-associated subpopulations that recapitulate neurodevelopmental processes and are associated with clinical outcomes. We identify discrete photoreceptor-like cells in MB subgroups GP3 and GP4 and nodule-associated neuronally-differentiated cells in subgroup SHH. MB immune infiltrates consist of both developmentally-related neuron-pruning and antigen presenting myeloid cells. We show that this MB cellular diversity is recapitulated in genetically engineered mouse subgroup-specific models of MB. These findings advance our understanding of both the neoplastic and immune landscape of MB.