Neuroblastoma is a childhood tumor, resulting from uncontrolled growth of neuroblasts instead of developing into nerve cells. Since immune therapies have an increasing impact on the treatment and prognosis of neuroblastoma, this study focuses on the interaction between neuroblastoma and immune system and the role of RNA on susceptibility of neuroblastoma cells to immune cell killing of NK cells. Additionally, the role of NK-cell mediated antibody-dependent tumor cytotoxicity (by autoantibodies of children with a paraneoplastic opsoclonus-myoclonus syndrome (OMS)) has been studied.Neuroblastoma cells treated with IFN-gamma (as a proinflammatory control), poly (I:C) and total RNA induced TLR-3 and MHC I expression on gene and protein level. The effect of poly (I:C) was stronger than using total RNA and the RNA / poly (I:C) effect was potentiated by IFN-gamma. Blocking the TLR-3 receptor with TLR3/dsRNA complex inhibitor decreased the expression of MHC I suggesting that TLR-3 is crucial for the regulation of MHC I expression in neuroblastoma cells. Furthermore, co-culture of NK-92 and neuroblastoma cells showed cytotoxic effects of NK cells on NB cells. Pre-treatment of NB cells with poly (I:C) and RNA decreased this effect. In contrast, surface-binding IgG from OMS patients induced higher NK-cell mediated cytotoxicity in neuroblastoma cells than IgG from NB patients without OMS or IgG from healthy controls. Although OMS-IgG itself has slight cytotoxic effect on NB cells, the effect on the NB-mediated tumor cell cytotoxicity was significantly higher. To compare the effects of RNA on neuroblastoma cells with non-tumor neuronal cells, we used fetal autonomic neurons. Similar to neuroblastoma cells, increased expression of MHC I and TLR-3 could be seen in fetal autonomic neurons along with increased proliferation and decreased cytotoxicity upon treatment with poly(I:C) and RNA. Multi-electrode array (MEA) measurements showed increased electrophysiological activity upon treatment with poly(I:C) and RNA in enteric neurospheres, indicating that free RNA and/or viral RNA could influence the electric function of neuronal cells. Our findings contribute to the knowledge of the role of RNA in interplay between tumor cells and the immune system.
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