Comparison of clinical grade type 1 polarized and standard matured dendritic cells for cancer immunotherapy

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• 作者：Morten Hansen^a ; ^{morten.hansen.01@regionh.dk} ; Gertrud Malene Hjort&#248 ; ^b ; Marco Donia^a ; ^c ; Ö ; zcan Met^a ; ^d ; Niels Bent Larsen^b ; Mads Hald Andersen^a ; Per thor Straten^a ; Inge Marie Svane^a ; ^d
• 关键词：¦ÁDC1s ; alpha-type-1-polarized DCs ; mDCs ; MPL ; IFN-¦Ã DCs ; mpDCs ; MPL ; IFN-¦Ã ; PGE2 DCs ; MPL ; monophosphoryl lipid A ; sDCs ; TNF-¦Á ; IL-1¦Â ; IL-6 ; PGE2 DCs
• 刊名：Vaccine
• 出版年：2013
• 出版时间：11 January, 2013
• 年：2013
• 卷：31
• 期：4
• 页码：639-646
• 全文大小：941 K

文摘

Monocyte-derived dendritic cells (DCs) used for immunotherapy e.g. against cancer are commonly matured by pro-inflammatory cytokines (TNF-¦Á, IL-1¦Â, IL-6) and prostaglandin E₂ 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 ¡°¦ÁDC1s¡± (TNF-¦Á, IL-1¦Â, IFN-¦Ã, IFN-¦Á, Poly(I:C)) and ¡°mDCs¡± (monophosphoryl lipid A (MPL), IFN-¦Ã) or a mixed cocktail - ¡°mpDCs¡±, containing MPL, IFN-¦Ã and PGE₂. ¦ÁDC1s 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. ¦ÁDC1s and mDCs were functionally superior to sDCs as they polarized na?ve 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. ¦ÁDC1s 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.