Pediatric Tumors-Mediated Inhibitory Effect on NK Cells: The Case of Neuroblastoma and Wilms’ Tumors

SIMPLE SUMMARY: Neuroblastoma (NB) and Wilms’ tumor (WT) are the most common childhood solid extracranial tumors. The current treatments consist of a combination of surgery and chemotherapy or radiotherapy in high-risk patients. Such treatments are responsible for significant adverse events requiring long-term monitoring. Thus, a main challenge in NB and WT treatment is the development of novel therapeutic strategies to eliminate or minimize the adverse effects. The characterization of the immune environment could allow for the identification of new therapeutic targets. Herein, we described the interaction between these tumors and innate immune cells, in particular natural killer cells and monocytes. The detection of the immunosuppressive activity of specific NB and WT tumor cells on natural killer cells and on monocytes could offer novel cellular and molecular targets for an effective immunotherapy of NB and WT. ABSTRACT: Natural killer (NK) cells play a key role in the control of cancer development, progression and metastatic dissemination. However, tumor cells develop an array of strategies capable of impairing the activation and function of the immune system, including NK cells. In this context, a major event is represented by the establishment of an immunosuppressive tumor microenvironment (TME) composed of stromal cells, myeloid-derived suppressor cells, tumor-associated macrophages, regulatory T cells and cancer cells themselves. The different immunoregulatory cells infiltrating the TME, through the release of several immunosuppressive molecules or by cell-to-cell interactions, cause an impairment of the recruitment of NK cells and other lymphocytes with effector functions. The different mechanisms by which stromal and tumor cells impair NK cell function have been particularly explored in adult solid tumors and, in less depth, investigated and discussed in a pediatric setting. In this review, we will compare pediatric and adult solid malignancies concerning the respective mechanisms of NK cell inhibition, highlighting novel key data in neuroblastoma and Wilms’ tumor, two of the most frequent pediatric extracranial solid tumors. Indeed, both tumors are characterized by the presence of stromal cells acting through the release of immunosuppressive molecules. In addition, specific tumor cell subsets inhibit NK cell cytotoxic function by cell-to-cell contact mechanisms likely controlled by the transcriptional coactivator TAZ. These findings could lead to a more performant diagnostic approach and to the development of novel immunotherapeutic strategies targeting the identified cellular and molecular targets.