Chromosomal instability degrades developmental phenotypes essential for anti-GD2 immunotherapy outcomes in high-risk neuroblastoma

High-risk neuroblastoma (HR-NBL) is a pediatric malignancy that arises during sympathoadrenal development and expresses the surface disialoganglioside GD2. Monoclonal anti-GD2 immunotherapy is a mainstay of HR-NBL treatment; however, it is associated with severe toxicities. Genomic correlates of outcomes following multimodality therapy containing anti-GD2 immunotherapy are limited. We profile 840 tumors and identify actionable ALK gene fusions in HR-NBL. We leverage fetal sympathoadrenal single-cell RNA sequencing to characterize patients with improved post-multimodality outcomes. We demonstrate that patients with improved outcomes have tumors that upregulate noradrenergic and metabolic phenotypes characteristic of mature sympathoblasts-a fetal sympathoadrenal cell population. We show that loss of these developmental phenotypes is mediated by chromosome 11q loss. Targeted analysis of 19 biopsy pairs identifies significant clonal evolution and accumulation of cell-cycle mutations following multimodality treatment. Collectively, we identify chromosomal instability-specifically 11q loss-as key in degrading developmental phenotypes critical for outcomes following multimodality therapy containing anti-GD2 immunotherapy.