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-Type-1 Polarized Dendritic Cells

A Novel Immunization Tool with Optimized CTL-inducing Activity

Departments of ¹ Surgery, ² Immunology, ³ Infectious Diseases and Microbiology, and ⁴ Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania; ⁵ Clinical Immunotherapy Group, University of Newcastle upon Tyne, United Kingdom, ⁶ Departments of Cell Biology and Dermatology, University of Amsterdam, the Netherlands; and the ⁷ University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania

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- and polyinosinic:polycytidylic acid (p-I:C) synergize with the "classical" type-1-polarizing cytokine cocktail [tumor necrosis factor (TNF)/IL-1ß/IFN], allowing for serum-free generation of fully mature type-1-polarized DCs (DC1). Such "-type-1-polarized DC(s)" (DC1) show high migratory responses to the CCR7 ligand, 6C-kine but produce much higher levels of IL-12p70 as compared to TNF/IL-1ß/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 DC1 (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 DC1 allows, for the first time, the clinical application of DCs that combine the key three features important for their efficacy as anticancer vaccines.

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