An Immune Microenvironment-Associated Gene Signature Predicts Outcomes and Therapeutic Response in Pediatric Medulloblastoma

Abstract Purpose: The tumor microenvironment (TME) is a pivotal factor in the progression and treatment response of cancers, including medulloblastoma (MB), the most common malignant brain tumor in children. This study investigates TME-specific gene signatures to create a prognostic model for MB patient outcomes. Methods: We sequenced 240 MB patient samples at Beijing Tiantan Hospital with RNASeq and analyzed TME components. Through co-expression network analysis and regression models, we identified an eight-gene signature that correlated with TME elements. This signature was tested against an independent dataset (GSE85217) for validation. Results: Our study presents the TME-associated risk score (TMErisk), which incorporates the eight-gene ( CEBPB , OLFML2B , GGTA1 , GZMA , TCIM , OLFML3 , NAT1 , and CD1C ) signature. Higher TMErisk scores were associated with decreased overall survival and lower immune cell infiltration, immune checkpoint activity, and human leukocyte antigen expression. There was also a notable negative correlation between TMErisk scores and both TMB and IPS, varying across MB molecular subtypes. Moreover, the TME-risk was inversely related to the tumor mRNAsi, implying the influence of the TME on tumor stemness. Conclusions: Our findings identify a TME-specific eight-gene prognostic model that may serve as a predictive biomarker for MB patient outcomes and responses to immunotherapy. This gene signature model offers a supplementary tool to current WHO molecular subtypes and provides a potential target for future TME-focused MB treatment strategies. However, the distinct TME landscapes across MB subtypes pose new challenges for further research. Keywords: gene signature, immune cells, medulloblastoma, tumor microenvironment, prognostic model, tumor, stromal cells