In Vivo Silencing of A20 via TLR9-Mediated Targeted SiRNA Delivery Potentiates Antitumor Immune Response

PloS One
Floriane C M BraunPiotr Grabarczyk

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 st...Continue Reading

References

May 21, 1999·Science·J A HoffmannR A Ezekowitz
Nov 5, 2002·Nature Reviews. Cancer·Mark J SmythHideo Yagita
Feb 4, 2003·Nature Reviews. Immunology·Giorgio Trinchieri
May 3, 2003·Molecular Therapy : the Journal of the American Society of Gene Therapy·William M SidersJohanne M Kaplan
Nov 19, 2003·Current Opinion in Oncology·James E Wooldridge, George J Weiner
Apr 2, 2004·Nature Reviews. Immunology·Dennis M Klinman
Apr 6, 2004·Nature Immunology·Etienne MeylanJürg Tschopp
Jan 18, 2005·Trends in Biochemical Sciences·Karen Heyninck, Rudi Beyaert
Dec 1, 2006·Annual Review of Immunology·Gabriel A RabinovichEduardo M Sotomayor
Dec 7, 2007·The Journal of Clinical Investigation·James O McNamaraEli Gilboa
Jan 7, 2009·The Journal of Immunology : Official Journal of the American Association of Immunologists·Karine BreckpotKris Thielemans
Apr 22, 2009·The Journal of Experimental Medicine·Barbara A Malynn, Averil Ma
Jun 6, 2009·Annual Review of Biochemistry·Brian SkaugZhijian J Chen
Apr 30, 2010·Bioorganic & Medicinal Chemistry·S M Abdur RahmanSatoshi Obika
Jun 10, 2010·The Journal of Experimental Medicine·Lars VereeckeGeert van Loo
Aug 2, 2011·International Journal of Oncology·Masahiro KatsudaHiroki Yamaue
Aug 30, 2011·Nature Genetics·Flavius Martin, Vishva M Dixit
Dec 18, 2013·Cell Reports·Christof FellmannJohannes Zuber
Jun 4, 2014·The Journal of Clinical Investigation·Andreas HerrmannHua Yu
Jul 16, 2014·Proceedings of the National Academy of Sciences of the United States of America·Marilyn GiordanoGrégory Verdeil

❮ Previous
Next ❯

Citations

Apr 17, 2016·Nucleic Acids Research·Rudolph L Juliano
Mar 18, 2016·PloS One·Tatyana O KabilovaElena L Chernolovskaya
Feb 8, 2020·Journal of Cellular Physiology·Hanwen LiXiawei Wei
Dec 11, 2020·Journal for Immunotherapy of Cancer·Weinan GuoChunying Li
May 3, 2021·Cancer Letters·Yongyu ShiLining Zhang

❮ Previous
Next ❯

Datasets Mentioned

BETA
GM-CSF

Methods Mentioned

BETA
FCS
fluorescence
FACS
flow cytometry
confocal microscopy
PCR
gene knockdown

Software Mentioned

Cell Quest Pro
ImageJ
SAS

Related Concepts

Related Feeds

Arterial-Venous in Development & Disease

Arterial-venous development may play a crucial role in cardiovascular diseases. Here is the latest research.

Antigenic Modulation

Antigenic modulation occurs when an antibody cross-links antigens on a cell surface, causing the antigens to become internalized. This can lead to therapeutic failure of monoclonal antibodies as the expression of the antigen becomes decreased on target cells. Find the latest research on antigenic modulation here.

Autoimmune Diseases

Autoimmune diseases occur as a result of an attack by the immune system on the body’s own tissues resulting in damage and dysfunction. There are different types of autoimmune diseases, in which there is a complex and unknown interaction between genetics and the environment. Discover the latest research on autoimmune diseases here.

Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis