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- Title
In vivo delivery of siRNA to immune cells by conjugation to a TLR9 agonist enhances antitumor immune responses.
- Authors
Kortylewski, Marcin; Swiderski, Piotr; Herrmann, Andreas; Lin Wang; Kowolik, Claudia; Kujawski, Maciej; Heehyoung Lee; Scuto, Anna; Yong Liu; Chunmei Yang; Jiehui Deng; Soifer, Harris S.; Raubitschek, Andrew; Forman, Stephen; Rossi, John J.; Pardoll, Drew M.; Jove, Richard; Hua Yu
- Abstract
Efficient delivery of small interfering (si)RNA to specific cell populations in vivo remains a formidable challenge to its successful therapeutic application. We show that siRNA synthetically linked to a CpG oligonucleotide agonist of toll-like receptor (TLR)9 targets and silences genes in TLR9+ myeloid cells and B cells, both of which are key components of the tumor microenvironment. When a CpG-conjugated siRNA that targets the immune suppressor gene Stat3 is injected in mice either locally at the tumor site or intravenously, it enters tumor-associated dendritic cells, macrophages and B cells. Silencing of Stat3 leads to activation of tumor-associated immune cells and ultimately to potent antitumor 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.
- Subjects
SMALL interfering RNA; CELL populations; THERAPEUTICS; OLIGONUCLEOTIDES; CHEMICAL agonists; B cells; DENDRITIC cells
- Publication
Nature Biotechnology, 2009, Vol 27, Issue 10, p925
- ISSN
1087-0156
- Publication type
Article
- DOI
10.1038/nbt.1564