Wilms’ Tumor Primary Cells Display Potent Immunoregulatory Properties on NK Cells and Macrophages

SIMPLE SUMMARY: Wilms’ tumor (WT) is the most common childhood renal tumor accounting for approximately 7% of childhood malignancies. The overall survival rate for patients with favorable histology is greater than 90% while the survival rate for patients with poor prognostic factors is around 50%. The current treatments consist in a combination of surgery and chemotherapy or radiotherapy in high risk patients. Such treatments are responsible for significant adverse effects requiring long-term monitoring. Thus, a main challenge in WT treatment is the development of novel therapeutic strategies to eliminate or minimize the adverse effects. The characterization of an immune environment could allow the identification of new therapeutic targets. Herein we studied the interaction between WT and innate immune cells, in particular NK cells and monocytes. Although WT are highly susceptible to NK-mediated lysis, the detection of immunoregulatory activity of WT tumor cells on NK cells and also on monocytes could offer novel cellular and molecular targets for an efficacious immunotherapy of WT. ABSTRACT: The immune response plays a crucial defensive role in cancer growth and metastasis and is a promising target in different tumors. The role of the immune system in Wilm’s Tumor (WT), a common pediatric renal malignancy, is still to be explored. The characterization of the immune environment in WT could allow the identification of new therapeutic strategies for targeting possible inhibitory mechanisms and/or lowering toxicity of the current treatments. In this study, we stabilized four WT primary cultures expressing either a blastematous (CD56(+)/CD133(−)) or an epithelial (CD56(−)/CD133(+)) phenotype and investigated their interactions with innate immune cells, namely NK cells and monocytes. We show that cytokine-activated NK cells efficiently kill WT cells. However, after co-culture with WT primary cells, NK cells displayed an impaired cytotoxic activity, decreased production of IFNγ and expression of CD107a, DNAM-1 and NKp30. Analysis of the effects of the interaction between WT cells and monocytes revealed their polarization towards alternatively activated macrophages (M2) that, in turn, further impaired NK cell functions. In conclusion, we show that both WT blastematous and epithelial components may contribute directly and indirectly to a tumor immunosuppressive microenvironment that is likely to play a role in tumor progression.