The neuroblastoma tumor microenvironment: From an in-depth characterization towards novel therapies

Neuroblastoma is a cancer of the sympathetic nervous system that develops in young children, either as low-risk or high-risk disease. The tumor microenvironment (TME) is now recognized as an important player of the tumor ecosystem that may promote drug resistance and immune escape. Targeting the TME in combination with therapies directly targeting tumor cells therefore represents an interesting strategy to prevent the emergence of resistance in cancer and improve patient's outcome. The development of such strategies however requires an in-depth understanding of the TME landscape, due to its high complexity and intra and inter-tumoral heterogeneity. Various approaches have been used in the last years to characterize the immune and non-immune cell populations present in tumors of neuroblastoma patients, both quantitatively and qualitatively, in particular with the use of single-cell transcriptomics. It is anticipated that in the near future, both genomic and TME information in tumors will contribute to a precise approach to therapy in neuroblastoma. Deciphering the mechanisms of interaction between neuroblastoma cells and stromal or immune cells in the TME is key to identify novel therapeutic combinations. Over the last decade, numerous in vitro studies and in vivo pre-clinical experiments in immune-competent and immune-deficient models have identified therapeutic approaches to circumvent drug resistance and immune escape. Some of these studies have formed the basis for early phase I and II clinical trials in children with recurrent and refractory high-risk neuroblastoma. This review summarizes recently published data on the characterization of the TME landscape in neuroblastoma and novel strategies targeting various TME cellular components, molecules and pathways activated as a result of the tumor-host interactions.