Single-Cell Profiling of the Microenvironment in High-Risk Neuroblastoma

Although tumor biology and treatment of neuroblastoma (NB) have substantially advanced, the clinical outcomes of patients with high-risk NB (HR-NB) still remain unsatisfactory. Increasing evidence suggests that targeting the tumor microenvironment (TME) is an effective strategy for the treatment of patients with HR-NB, highlighting the necessity to deepen the understanding of the complex TME in HR-NB. We analyzed the single-cell RNA sequencing data of 16 NB samples from 11 patients with HR-NB and 5 patients with intermediate-/low-risk NB. We found that proliferating CD8+ TUBA1B+ T cells, H2AFZ+ macrophages, and proliferating HMGB2+ B cells were particularly enriched in HR-NB samples and played an immunosuppressive role. LAG3 and HAVCR2 could serve as potential immunotherapeutic targets for HR-NB. SCENIC analysis innovatively revealed that proliferating HMGB2+ B cells had a special differentiation process compared with that of plasma cells. H2AFZ+ macrophages evolved from monocytes and M1-like macrophages and exhibited an M2-like phenotype. HR-NB-enriched cancer-associated fibroblasts and endothelial cells were related to tumor migration and progression. An immune-related risk model based on five genes (BIRC5, UBE2C, CDKN3, TK1, and PTTG1) was constructed in the training set and applied to the validation set. Both sets showed a promising clinical prediction value. In sum, this study preliminarily revealed the landscape of the TME in HR-NB at a single-cell level; several TME cell clusters that could inhibit immune activities or promote tumor progression in HR-NB were determined, thereby providing novel immunotherapeutic targets and an immune-related prognostic signature for HR-NB and promoting the development of immunotherapy of HR-NB.