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In Vivo Silencing of A20 via TLR9-Mediated Targeted SiRNA Delivery Potentiates Antitumor Immune Response
Authors:Floriane C M Braun  Jens van den Brandt  S?ren Thomas  Sandra Lange  Juliane Schrank  Claudia Gand  Grzegorz K Przybylski  Katrin Schmoeckel  Barbara M Br?ker  Christian A Schmidt  Piotr Grabarczyk
Institution:1. Clinic of Internal Medicine C, Department of Molecular Hematology, University Medicine Greifswald, Greifswald, Germany.; 2. Central Core & Research Facility of Laboratory Animals, University of Greifswald, Greifswald, Germany.; 3. Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland.; 4. Institute of Immunology and Transfusion Medicine, University of Greifswald, Greifswald, Germany.; Leiden University Medical Center, NETHERLANDS,
Abstract:A20 is an ubiquitin-editing enzyme that ensures the transient nature of inflammatory signaling pathways induced by cytokines like TNF-α and IL-1 or pathogens via Toll-like receptor (TLR) pathways. It has been identified as a negative regulator of dendritic cell (DC) maturation and attenuator of their immunostimulatory properties. Ex vivo A20-depleted dendritic cells showed enhanced expression of pro-inflammatory cytokines and costimulatory molecules, which resulted in hyperactivation of tumor-infiltrating T lymphocytes and inhibition of regulatory T cells. In the present study, we demonstrate that a synthetic molecule consisting of a CpG oligonucleotide TLR9 agonist linked to A20-specific siRNAs silences its expression in TLR9+ mouse dendritic cells in vitro and in vivo. In the B16 mouse melanoma tumor model, silencing of A20 enhances the CpG-triggered induction of NFκB activity followed by elevated expression of IL-6, TNF-α and IL-12. This leads to potentiated antitumor immune responses manifested by increased numbers of tumor-specific cytotoxic T cells, high levels of tumor cell apoptosis and delayed tumor growth. Our findings confirm the central role of A20 in controlling the immunostimulatory potency of DCs and provide a strategy for simultaneous A20 silencing and TLR activation in vivo.
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