The Tumor Microenvironment in Neuroblastoma: New Players, New Mechanisms of Interaction and New Perspectives

Simple Summary Neuroblastoma is the second most common solid tumor in children. Our understanding of the contribution of genetic factors (seed) that contribute to neuroblastoma progression has substantially improved in the last 2 decades but the contribution of the tumor microenvironment (TME, soil) is the subject of more recent attention. Here we highlight recent studies pointing to novel mechanisms by which the TME affects neuroblastoma progression. Cancer-associated fibroblasts are present in neuroblastoma tumors and contribute to escape from chemotherapy and immunotherapy. Extracellular vesicles and regulatory micro-RNAs they contain, serve as shuttle mechanisms between neuroblastoma cells and stromal cells. The TME landscape of neuroblastoma differs between MYCN amplified and MYCN-non amplified tumors with the former being "cold" and the latter "hot" and rich in inflammatory cells. These recent observations will have a significant impact on our ability to design precise clinical trials that integrate information on the neuroblastoma cells and on their TME. The contribution of the tumor microenvironment (TME) to cancer progression has been well recognized in recent decades. As cancer therapeutic strategies are increasingly precise and include immunotherapies, knowledge of the nature and function of the TME in a tumor becomes essential. Our understanding of the TME in neuroblastoma (NB), the second most common solid tumor in children, has significantly progressed from an initial focus on its Schwannian component to a better awareness of its complex nature, which includes not only immune but also non-immune cells such as cancer-associated fibroblasts (CAFs), the contribution of which to inflammation and interaction with tumor-associated macrophages (TAMs) is now recognized. Recent studies on the TME landscape of NB tumors also suggest significant differences between MYCN-amplified (MYCN-A) and non-amplified (MYCN-NA) tumors, in their content in stromal and inflammatory cells and their immunosuppressive activity. Extracellular vesicles (EVs) released by cells in the TME and microRNAs (miRs) present in their cargo could play important roles in the communication between NB cells and the TME. This review article discusses these new aspects of the TME in NB and the impact that information on the TME landscape in NB will have in the design of precise, biomarker-integrated clinical trials.