A longitudinal single-cell and spatial multiomic atlas of pediatric high-grade glioma

Pediatric high-grade glioma (pHGG) is an incurable central nervous system malignancy that is a leading cause of pediatric cancer death. While pHGG shares many similarities to adult glioma, it comprises distinct disease entities. In this study, we longitudinally profiled a molecularly diverse cohort of 16 pHGG patients through single-nucleus RNA and ATAC sequencing, whole-genome sequencing, and CODEX spatial proteomics to capture the evolution of the tumor microenvironment during progression following treatment. We defined a set of pan-pHGG neoplastic cell states and observed differential tumor-myeloid interactions between malignant cell phenotypes. We found that essential neuromodulators and the interferon response are upregulated post-therapy and validated malignant cell-intrinsic targets. We found that there is an increase in oligodendrocytes upon progression and that they coordinate spatial motifs with proneural tumor cells. This multiomic atlas of longitudinal pHGG captures the key features of therapy response and provides a scalable reference for the study of pediatric brain tumors.