Neuroblastoma-derived gangliosides inhibit dendritic cell generation and function

Neuroblastoma (NB), a tumor of the sympathetic nervous system, is the most common extracranial solid tumor in children. NB-derived gangliosides inhibi t the functional activity of T and natural killer cells, contribute to tumo r-induced bone marrow suppression, and cause multiple alterations of hemato poiesis, resulting in pancytopenia. However, the role of gangliosides in th e regulation of dendritic cell (DC) generation (dendropoiesis) has not been studied. Using murine and human NB cell lines, we demonstrated that coincu bation of murine bone marrow progenitors or human CD34+ progenitor cells wi th NB cells resulted in a significant inhibition of dendropoiesis in vitro up to 90%. The number of DCs was assessed by FACScan determination of CD83 or CD11c+ cells coexpressing MHC class II and CD86 molecules. In addition, inhibition of antigen-presenting properties of DCs cultured in the presenc e of NB cells was observed in allogeneic mixed leukocyte reaction (33,508 /- 1,613 cpm for control DCs versus 17,428 +/- 152 cpm for NB-treated DCs; P < 0.05). Treatment of NB cells with 10 <mu>M DL-threo-1-phenyl-2-decanoly lamine-3-morpholino-1-propanol HCl, an inhibitor of glucosylceramide syntha se, markedly abrogated ganglioside synthesis and was accompanied by blockad e of NB ability to inhibit dendropoiesis. Furthermore, purified ganglioside s added to DC cultures significantly inhibited DC generation. The percentag e of CD83+ cells decreased from 51.8 +/- 6.1% in the control group to 12.9 +/- 2.7% in cultures treated with G(D2) (P < 0.05). Thus, our results demon strate that NB-derived gangliosides inhibit the generation of functionally active DCs and may play a role in tumor-induced immunosuppression and subse quent tumor escape from immune recognition and elimination.