Characterizing the B-cell Receptor Landscape Across Pediatric Brain Tumors

Introduction: Brain tumors are the leading cause of cancer-related deaths in children. B lymphocytes are essential in adaptive immunity, with each cell expressing a highly specific receptor (BCR) to recognize foreign antigens. While B-cells are present in pediatric brain tumors, their molecular identities, phenotypes, and functions remain poorly understood.

Methods: We developed bcRflow, a Nextflow pipeline to characterize BCR repertoires from non-targeted transcriptomic data. Applying this to approximately 1,000 molecularly characterized pediatric brain tumors, we examined BCR isotype distribution, IGH-V gene expression, affinity maturation, and clonal expansion. Diversity was measured using Hill numbers, Pielou’s evenness, and Shannon indices, while clonal expansion was assessed via Chao1 and ACE indices. These features were correlated with immunosuppressive gene expression signatures.

Results: Significant variations in BCR repertoire architecture emerged across tumor types. For instance, atypical teratoid rhabdoid tumor (ATRT) samples exhibited high diversity, reflected by elevated Shannon, D50, and Hill diversity indices, and a balanced mix of rare and abundant clonotypes based on high Pielou’s evenness and ACE indices. Moderate class switching and somatic hypermutation suggest heterogenous B-cell activation shaped by immunosuppressive tumor microenvironments. TNFSF13B expression was moderately increased across seven tumor types, potentially supporting tumor growth through immunosuppression mechanisms. Among IGH-V genes, IGHV3-23, IGHV3-30, and IGHV3-48 displayed the highest transcriptional activity across all tumor types, suggesting enhanced affinity maturation in response to tumor-associated antigens.

Conclusion : Our analysis reveals distinct immunological profiles across tumor types, with marked differences in clonal diversity and adaptive response potential. ATRT samples demonstrate a complex immune environment with increased BCR diversity and clonal expansion compared with other tumor types, suggesting an antigen-driven clonal selection. Investigating how gene expression signatures correlate to the functions of different B-cells and tertiary lymphoid structures is ongoing. Insights into these unique BCR repertoires could inform the design of novel immunotherapies, enabling more targeted and personalized treatment options.