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TLR agonist–Stat3 siRNA conjugates: cell-specific gene silencing and enhanced antitumor immune responses
Efficient delivery of siRNA to specific cell populations in vivo remains a formidable challenge to its successful therapeutic application. We describe a novel siRNA-based approach – synthetically linking siRNA to an oligonucleotide TLR9 agonist – that targets and silences genes in TLR9(+) myeloid ce...
Autores principales: | , , , , , , , , , , , , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
Publicado: |
2009
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2846721/ https://www.ncbi.nlm.nih.gov/pubmed/19749770 http://dx.doi.org/10.1038/nbt.1564 |
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author | Kortylewski, Marcin Swiderski, Piotr Herrmann, Andreas Wang, Lin Kowolik, Claudia Kujawski, Maciej Lee, Heehyoung Scuto, Anna Liu, Yong Yang, Chunmei Deng, Jiehui Soifer, Harris S. Raubitschek, Andrew Forman, Stephen Rossi, John J. Pardoll, Drew M. Jove, Richard Yu, Hua |
author_facet | Kortylewski, Marcin Swiderski, Piotr Herrmann, Andreas Wang, Lin Kowolik, Claudia Kujawski, Maciej Lee, Heehyoung Scuto, Anna Liu, Yong Yang, Chunmei Deng, Jiehui Soifer, Harris S. Raubitschek, Andrew Forman, Stephen Rossi, John J. Pardoll, Drew M. Jove, Richard Yu, Hua |
author_sort | Kortylewski, Marcin |
collection | PubMed |
description | Efficient delivery of siRNA to specific cell populations in vivo remains a formidable challenge to its successful therapeutic application. We describe a novel siRNA-based approach – synthetically linking siRNA to an oligonucleotide TLR9 agonist – that targets and silences genes in TLR9(+) myeloid cells and B cells, both of which are key components of the tumor microenvironment. Because Stat3 in tumor-associated immune cells suppresses antitumor immune responses and hinders TLR9-induced immune stimulation, we tested CpG-Stat3siRNA conjugates for anti-tumor effects. When injected locally at the tumor site or systemically through an intravenous route, the CpG-Stat3siRNA conjugates access tumor-associated dendritic cells, macrophages and B cells, inhibit Stat3 expression, leading to activation of tumor-associated immune cells, and ultimately potent anti-tumor immune responses. Our findings demonstrate the potential of TLR agonist-siRNA conjugates for targeted gene silencing coupled with TLR stimulation and immune activation in the tumor microenvironment. |
format | Text |
id | pubmed-2846721 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2009 |
record_format | MEDLINE/PubMed |
spelling | pubmed-28467212010-04-01 TLR agonist–Stat3 siRNA conjugates: cell-specific gene silencing and enhanced antitumor immune responses Kortylewski, Marcin Swiderski, Piotr Herrmann, Andreas Wang, Lin Kowolik, Claudia Kujawski, Maciej Lee, Heehyoung Scuto, Anna Liu, Yong Yang, Chunmei Deng, Jiehui Soifer, Harris S. Raubitschek, Andrew Forman, Stephen Rossi, John J. Pardoll, Drew M. Jove, Richard Yu, Hua Nat Biotechnol Article Efficient delivery of siRNA to specific cell populations in vivo remains a formidable challenge to its successful therapeutic application. We describe a novel siRNA-based approach – synthetically linking siRNA to an oligonucleotide TLR9 agonist – that targets and silences genes in TLR9(+) myeloid cells and B cells, both of which are key components of the tumor microenvironment. Because Stat3 in tumor-associated immune cells suppresses antitumor immune responses and hinders TLR9-induced immune stimulation, we tested CpG-Stat3siRNA conjugates for anti-tumor effects. When injected locally at the tumor site or systemically through an intravenous route, the CpG-Stat3siRNA conjugates access tumor-associated dendritic cells, macrophages and B cells, inhibit Stat3 expression, leading to activation of tumor-associated immune cells, and ultimately potent anti-tumor immune responses. Our findings demonstrate the potential of TLR agonist-siRNA conjugates for targeted gene silencing coupled with TLR stimulation and immune activation in the tumor microenvironment. 2009-09-13 2009-10 /pmc/articles/PMC2846721/ /pubmed/19749770 http://dx.doi.org/10.1038/nbt.1564 Text en http://www.nature.com/authors/editorial_policies/license.html#terms Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms |
spellingShingle | Article Kortylewski, Marcin Swiderski, Piotr Herrmann, Andreas Wang, Lin Kowolik, Claudia Kujawski, Maciej Lee, Heehyoung Scuto, Anna Liu, Yong Yang, Chunmei Deng, Jiehui Soifer, Harris S. Raubitschek, Andrew Forman, Stephen Rossi, John J. Pardoll, Drew M. Jove, Richard Yu, Hua TLR agonist–Stat3 siRNA conjugates: cell-specific gene silencing and enhanced antitumor immune responses |
title | TLR agonist–Stat3 siRNA conjugates: cell-specific gene silencing and enhanced antitumor immune responses |
title_full | TLR agonist–Stat3 siRNA conjugates: cell-specific gene silencing and enhanced antitumor immune responses |
title_fullStr | TLR agonist–Stat3 siRNA conjugates: cell-specific gene silencing and enhanced antitumor immune responses |
title_full_unstemmed | TLR agonist–Stat3 siRNA conjugates: cell-specific gene silencing and enhanced antitumor immune responses |
title_short | TLR agonist–Stat3 siRNA conjugates: cell-specific gene silencing and enhanced antitumor immune responses |
title_sort | tlr agonist–stat3 sirna conjugates: cell-specific gene silencing and enhanced antitumor immune responses |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2846721/ https://www.ncbi.nlm.nih.gov/pubmed/19749770 http://dx.doi.org/10.1038/nbt.1564 |
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