The immune cell atlas of human neuroblastoma

Our current knowledge of the different immune cells in neuroblastoma is based on in vitro and in vivo studies mainly focusing on a single cell type. Importantly, different studies have conveyed conflicting results. Moreover, a comprehensive immune cell overview at the single-cell level is still missing and understanding the complete immune cell composition of neuroblastoma will be crucial for the development of novel immunotherapeutics against the disease. In this study, we performed single-cell RNA-sequencing on nineteen human neuroblastoma samples coupled with multiplex immunohistochemistry and survival analysis using additional datasets to provide a comprehensive cellular and molecular immune cell landscape of human neuroblastoma. Further, we contrasted our data with single-cell RNA-sequencing data from normal fetal adrenal gland to characterize cell-state changes from normal tissue to cancerous neuroblastoma. Our analysis revealed 27 immune cell subtypes including distinct subpopulations of myeloid, NK, B and T cells not identified in neuroblastoma before. Several immune cell subtypes demonstrated a survival benefit such as inflammatory monocytes, tumor associated macrophages, various T cell populations, and Active NK cells. Furthermore, in contrast to adult cancers and previous neuroblastoma studies, we demonstrated an increase in inflammatory monocyte cell-state when contrasting normal and tumor tissue, while we do not observe differences in cytotoxicity and exhaustion score for cytotoxic T cells, nor in Treg activity. Finally, we performed a systemic receptor-ligand interaction analysis between tumor, stroma and immune cells, where we showed the neuroblastoma tumor microenvironment is highly complex and strongly correlated to survival. In addition, we highlighted several interactions that we suggest to be tested in future studies as a therapeutic option in human neuroblastoma. Taken together, our study significantly adds to the in depth understanding of the immune cell landscape, the complexity of the tumor microenvironment and it provides a resource for the development of novel immunotherapeutics for neuroblastoma.

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