The clinical grade maturation cocktail monophosphoryl lipid A plus IFNgamma generates monocyte-derived dendritic cells with the capacity to migrate and induce Th1 polarization

Abstract

Ex vivo generated monocyte-derived dendritic cells (DCs) are used as a cellular vaccine against cancer in clinical trials. In order to be able to induce an efficient tumour-specific CTL response during immunotherapy, DCs have to be able to migrate to the lymph node and produce the Th1 polarizing cytokine, IL-12p70, upon encounter of T cells in the lymph node. However, most clinically used DCs do not produce IL-12p70 upon T cell contact. In this study, we compared a newly developed clinical grade DC maturation cocktail consisting of MPLA and IFNgamma with two clinically available maturation cocktails, the 'gold standard' (TNFalpha, IL-1beta, IL-6 and PGE(2)) and the 'alpha type 1 polarizing' (TNFalpha, IL-1beta, IFNalpha, IFNgamma and pI:C) cocktail. All three cocktails induced phenotypically mature DCs. However, in contrast to 'gold standard' DCs, which produce no IL-12p70 and as a result induce mainly Th2 cells, DCs matured with MPLA and IFNgamma produce high levels of IL-12p70 upon CD40 triggering. Subsequently, these DCs induce mainly Th1 cells in vitro, even slightly more than by the alpha type 1 polarized DCs. In addition, MPLA plus IFNgamma matured DCs have an intermediate migratory capacity towards CCL21. In conclusion, we here present MPLA plus IFNgamma as a simple clinical grade maturation cocktail to generate immunostimulatory DCs with superior capacity to induce type 1 immunity.