Neuroblastoma-induced inhibition of dendritic cell IL-12 production via abrogation of CD40 expression.
OBJECTIVE
CD40 expression by dendritic cells (DCs) critically regulates their maturation/antitumor activity. CD40-CD40 ligand (CD40L) signaling stimulates DC-mediated IL-12 production/cytotoxicity. Recent studies suggest that neuroblastoma (NB)-derived gangliosides impair DC maturation, IL-12 secretion, and NK/T-cell activity. Neuroblastoma ganglioside-mediated abrogation of CD40 expression by DC and tumor-induced tolerance has not been studied. The purpose of this study is to determine if NB inhibits DC IL-12 production via CD40. The contributory role of the NB-derived ganglioside GM3 in this process is also examined.


METHODS
Dendritic cells were generated from bone marrow of mice injected with saline (control) or murine NB. Control DCs were matured with or without GM3. Dendritic cells were cocultured with NB cells treated with or without a ganglioside synthesis inhibitor. Dendritic cell groups were analyzed for maturation/costimulatory markers. Control and tumor-derived DC were stimulated with CD40L or Staphylococcus aureus and studied for IL-12 expression.


RESULTS
CD40 expression on DC generated from NB bearing mice decreased by 64% (P < .001). GM3 down-regulated DC maturation and CD40 expression. Only CD40-dependent IL-12 production was abrogated (60%, P < .01) in DC derived from NB-bearing mice. Dendritic cell capacity to synthesize IL-12 remained intact.


CONCLUSIONS
Neuroblastoma-induced inhibition of DC function may result from ganglioside-mediated CD40 signaling deficiency. Strategies to bypass/augment CD40-CD40L signaling may improve current NB immunotherapies.
Walker
Sonya R
SR
Division of Pediatric Surgery, Children's Hospital of Pittsburgh, Pittsburgh, PA 15213-2583, USA.
Redlinger
Richard E
RE
Barksdale
Edward M
EM
D000818:Animals; D019013:CD40 Antigens / Q000096:biosynthesis*; D023201:CD40 Ligand / Q000276:immunology; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation; D005679:G(M3) Ganglioside / Q000276:immunology* / Q000378:metabolism; D018664:Interleukin-12 / Q000096:biosynthesis*; D051379:Mice; D008815:Mice, Inbred Strains; D009423:Nervous System Neoplasms / Q000276:immunology*; D009447:Neuroblastoma / Q000276:immunology*; D015398:Signal Transduction
D019013:CD40 Antigens; D005679:G(M3) Ganglioside; D023201:CD40 Ligand; D018664:Interleukin-12