Interferon-γ dose-dependently inhibits prostaglandin E2-mediated dendritic-cell-migration towards secondary lymphoid organ chemokines

Monocyte-derived human dendritic cells (MoDCs) are increasingly applied as cellular vaccines for cancer patients. Important features for their efficacy include high migratory responsiveness to lymph node-chemokines and most likely their ability to produce bioactive IL-12 p70 upon subsequent contact with CD40 ligand-expressing T-cells. The current standard DC-maturation cocktail for clinical trials is inflammatory cytokines (TNF-α, IL-1β and IL-6) combined with prostaglandin E2 (PGE2), inducing phenotypically mature MoDCs with high migratory responsiveness to CCR7 ligands. This cocktail does not, however, induce or prime for production of IL-12 p70. Addition of IFN-γ to PGE2-containing maturation cocktails has been shown to prime for substantial production of IL-12 p70 by subsequent CD40 ligation, but the impact of IFN-γ on phenotypic maturation and migratory responsiveness induced by PGE2-containing inflammatory stimuli still remains elusive. Here, we demonstrate that addition of IFN-γ to the standard maturation cocktail decreased CCR7 mRNA and down-regulated CCR7 expression on MoDCs in a dose-dependent manner. Moreover, addition of IFN-γ was found to suppress MoDC-migration towards the CCR7-ligands CCL19 and CCL21. These novel findings indicate that addition of IFN-γ to DC-maturation stimuli may have no beneficial impact on MoDC-vaccine efficiency and further implicate IFN-γ as a negative feedback factor in DC migration towards draining lymph nodes when full-blown Th1-type responses are established. Such mechanism may restrict an uncontrolled and potentially harmful amplification of the adaptive Th1 response.