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

ABSTRACT 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.