Medulloblastoma immune microenvironment resembles early brain development and reveals novel basophil- B cell- associated signatures.

BACKGROUND: Medulloblastoma (MB) is the most common malignant pediatric brain tumor; yet, the mechanisms underlying immune evasion remain poorly understood. Since the developing brain's immune environment naturally promotes tissue tolerance and remodeling, we hypothesized that MB may exploit developmental immune programs to escape surveillance. Here, we aimed to characterize the immune microenvironment of MB compared to healthy brain tissue across different developmental stages.

METHODS: We analyzed RNA-sequencing data from 124 MB tumors and 47 control brain samples spanning postconception weeks (PCWs) 8-37 through adulthood. Using xCell and DeconRNAseq, we quantified enrichment scores for 34 immune cell types and compared their profiles.

RESULTS: MB tumors exhibited a distinct immune profile most similar to PCW controls among all age groups tested (P < .001). Key findings included significantly elevated basophils, neutrophils, immature dendritic cells, memory B cells, Th2 cells, and NKT cells in MB samples. Conversely, macrophages (M1 and M2 subtypes), matured dendritic cells, regulatory T cells, and most B cell populations showed reduced enrichment. This pattern suggests a Treg-independent immunosuppressive mechanism. Notably, basophil enrichment in MB was comparable to PCW samples but significantly higher than older controls, potentially explaining the concurrent elevation of memory B cells.

CONCLUSIONS: MB displays an immune microenvironment resembling early developmental stages, characterized by elevated basophils and memory B cells alongside reduced conventional immune surveillance mechanisms. These findings suggest that MB may co-opt developmental immune tolerance programs and highlight basophil - B cell interactions as potential therapeutic targets. The developmental similarity provides new insights into MB pathogenesis and immune evasion strategies.