Comparison of clinical grade type I polarized and standard matured dendritic cells for cancer immunotherapy

Monocyte-derived dendritic cells (DCs) used for immunotherapy e.g. against cancer are commonly matured by pro-inflammatory cytokines (TNF-alpha, IL-1 beta, IL-6) and prostaglandin E-2 although the absence of Toll-like receptor mediated activation prevents secretion of IL-12 from DCs and subsequent efficient induction of type 1 effector T cells. Standard matured clinical grade DCs sDCs were compared with DCs matured with either of two type 1 polarizing maturation cocktails; the alpha-type-1 DCs alpha DC1s (TNF-alpha, IL-1 beta, IFN-gamma, IFN-alpha, Poly(I:C)) and mDCs (monophosphoryl lipid A (MPL), IFN-gamma) or a mixed cocktail - mpDCs, containing MPL, IFN-gamma and PGE(2). alpha DC1s and mDCs secreted IL-12 directly and following re-stimulation with CD40L-expressing cells and they mainly secreted the T effector cell attracting chemokines CXCL10 and CCL5 as opposed to sDCs that mainly secreted CCL22, known to attract regulatory T cells. alpha DC1s and mDCs were functionally superior to sDCs as they polarized naive CD4(+) T cells most efficiently into T helper type 1 effector cells and primed more functional MART-1 specific CD8(+) T cells although with variation between donors. alpha DC1s and mDCs were transiently less capable of CCL21-directed transwell migration than standard matured DCs, likely due to their increased secretion of CCL19, which mediate internalization of CCR7. mpDCs were intermediate between standard and polarized DCs both in terms of IL-12 secretion and transwell migratory ability but functionally they resembled sDCs and strikingly had the highest expression of the inhibitory molecules PD-L1 and CD25. Thus, further studies with type 1 polarized DCs are warranted for use in immunotherapy, but when combined with PGE2 as in mpDCs, they seems to be less optimal for maturation of DCs. (C) 2012 Elsevier Ltd. All rights reserved.