Soluble factors derived from neuroblastoma cell lines suppress dendritic cell differentiation and activation

<jats:p>Dendritic cells (<jats:styled-content style="fixed-case">DC</jats:styled-content>) play a key role in the initiation of both antitumor immunity and immunological tolerance. It has been demonstrated that exposure to soluble factors produced by tumor cells modulates <jats:styled-content style="fixed-case">DC</jats:styled-content> functions and induces tolerogenic <jats:styled-content style="fixed-case">DC</jats:styled-content> differentiation. In this study, we investigated the effects of neuroblastoma cell line‐derived soluble factors on <jats:styled-content style="fixed-case">DC</jats:styled-content> differentiation. Monocytes isolated from healthy volunteers were incubated with interleukin (<jats:styled-content style="fixed-case">IL</jats:styled-content>)‐4 and granulocyte‐macrophage colony‐stimulating factor in the presence of culture supernatants from neuroblastoma cell lines. The culture supernatants from neuroblastoma cell lines, such as <jats:styled-content style="fixed-case">NLF</jats:styled-content> and <jats:styled-content style="fixed-case">GOTO</jats:styled-content>, partially blocked both downregulation of <jats:styled-content style="fixed-case">CD</jats:styled-content>14 and upregulation of <jats:styled-content style="fixed-case">CD</jats:styled-content>1a, and dramatically decreased <jats:styled-content style="fixed-case">IL</jats:styled-content>‐12 and tumor necrosis factor (<jats:styled-content style="fixed-case">TNF</jats:styled-content>)‐α production from mature <jats:styled-content style="fixed-case">DC</jats:styled-content>, while no effect of <jats:styled-content style="fixed-case">SH</jats:styled-content>‐<jats:styled-content style="fixed-case">SY</jats:styled-content>5Y cell supernatant was noted. In addition, <jats:styled-content style="fixed-case">IL</jats:styled-content>‐6 and <jats:styled-content style="fixed-case">IL</jats:styled-content>‐10 production from monocytes was increased by the supernatants of <jats:styled-content style="fixed-case">NLF</jats:styled-content> and <jats:styled-content style="fixed-case">GOTO</jats:styled-content> cells at 24 hours after incubation. Furthermore, we evaluated <jats:styled-content style="fixed-case">DC</jats:styled-content> functions through stimulation of invariant natural killer T (<jats:styled-content style="fixed-case">iNKT</jats:styled-content>) cells. α‐Galactosylceramide‐pulsed <jats:styled-content style="fixed-case">DC</jats:styled-content> co‐cultured with supernatants of <jats:styled-content style="fixed-case">NLF</jats:styled-content> cells were unable to sufficiently stimulate <jats:styled-content style="fixed-case">iNKT</jats:styled-content> cells. The decreased ability of <jats:styled-content style="fixed-case">iNKT</jats:styled-content> cells to produce interferon (<jats:styled-content style="fixed-case">IFN</jats:styled-content>)‐γ after stimulation with neuroblastoma cell line supernatant‐cultured <jats:styled-content style="fixed-case">DC</jats:styled-content> was reversed by addition of <jats:styled-content style="fixed-case">IL</jats:styled-content>‐12. <jats:styled-content style="fixed-case">CD</jats:styled-content>40 expression and <jats:styled-content style="fixed-case">IL</jats:styled-content>‐12 production in <jats:styled-content style="fixed-case">NLF</jats:styled-content>‐sup‐treated <jats:styled-content style="fixed-case">DC</jats:styled-content> were increased by addition of exogenous <jats:styled-content style="fixed-case">IFN</jats:styled-content>‐γ. These results indicate that tolerogenic <jats:styled-content style="fixed-case">DC</jats:styled-content> are induced in the neuroblastoma tumor microenvironment and attenuate the antitumor effects of <jats:styled-content style="fixed-case">iNKT</jats:styled-content> cells. Interactions between <jats:styled-content style="fixed-case">iNKT</jats:styled-content> cells and αGalCer‐pulsed <jats:styled-content style="fixed-case">DC</jats:styled-content> have the potential to restore the immunosuppression of tolerogenic <jats:styled-content style="fixed-case">DC</jats:styled-content> through <jats:styled-content style="fixed-case">IFN</jats:styled-content>‐γ production.</jats:p>