alpha-type-1 polarized dendritic cells: a novel immunization tool with optimized CTL-inducing activity.
Using the principle of functional polarization of dendritic cells (DCs), we have developed a novel protocol to generate human DCs combining the three features critical for the induction of type-1 immunity: (a) fully mature status; (b) responsiveness to secondary lymphoid organ chemokines; and (c) high interleukin-12p70 (IL-12p70)-producing ability. We show that IFN-alpha and polyinosinic:polycytidylic acid (p-I:C) synergize with the "classical" type-1-polarizing cytokine cocktail [tumor necrosis factor alpha (TNFalpha)/IL-1beta/IFNgamma], allowing for serum-free generation of fully mature type-1-polarized DCs (DC1). Such "alpha-type-1-polarized DC(s)" (alphaDC1) show high migratory responses to the CCR7 ligand, 6C-kine but produce much higher levels of IL-12p70 as compared to TNFalpha/IL-1beta/IL-6/prostaglandin E2 (PGE2)-matured DCs (sDC), the current "gold standard" in DC-based cancer vaccination. A single round of in vitro sensitization with alphaDC1 (versus sDCs) induces up to 40-fold higher numbers of long-lived CTLs against melanoma-associated antigens: MART-1, gp100, and tyrosinase. Serum-free generation of alphaDC1 allows, for the first time, the clinical application of DCs that combine the key three features important for their efficacy as anticancer vaccines.
Mailliard
Robbie B
RB
Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213-1863, USA.
Wankowicz-Kalinska
Anna
A
Cai
Quan
Q
Wesa
Amy
A
Hilkens
Catharien M
CM
Kapsenberg
Martien L
ML
Kirkwood
John M
JM
Storkus
Walter J
WJ
Kalinski
Pawel
P
D016764:Cell Polarity / Q000276:immunology; D002633:Chemotaxis / Q000276:immunology; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D016898:Interferon-alpha / Q000276:immunology / Q000494:pharmacology; D007371:Interferon-gamma / Q000276:immunology / Q000494:pharmacology; D007375:Interleukin-1 / Q000276:immunology / Q000494:pharmacology; D018664:Interleukin-12 / Q000096:biosynthesis / Q000276:immunology; D008024:Ligands; D008545:Melanoma / Q000097:blood / Q000276:immunology; D011070:Poly I-C / Q000276:immunology / Q000494:pharmacology; D021122:Protein Subunits / Q000096:biosynthesis / Q000276:immunology; D054400:Receptors, CCR7; D019707:Receptors, Chemokine / Q000276:immunology / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000494:pharmacology
C515370:CCR7 protein, human; D016898:Interferon-alpha; D007375:Interleukin-1; D008024:Ligands; D021122:Protein Subunits; D054400:Receptors, CCR7; D019707:Receptors, Chemokine; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D007371:Interferon-gamma; D011070:Poly I-C