Research abstract
Article abstract
Nature Biotechnology 27, 925 - 932 (2009)
Published online: 13 September 2009 | doi:10.1038/nbt.1564
In vivo delivery of siRNA to immune cells by conjugation to a TLR9 agonist enhances antitumor immune responses
Marcin Kortylewski1, Piotr Swiderski2, Andreas Herrmann1, Lin Wang1, Claudia Kowolik2, Maciej Kujawski1, Heehyoung Lee1, Anna Scuto2, Yong Liu1, Chunmei Yang1, Jiehui Deng1, Harris S Soifer3, Andrew Raubitschek1, Stephen Forman4, John J Rossi3, Drew M Pardoll5, Richard Jove2 & Hua Yu1
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.
- Departments of Cancer Immunotherapeutics & Tumor Immunology, Beckman Research Institute at City of Hope, Duarte, California, USA.
- Molecular Medicine, Beckman Research Institute at City of Hope, Duarte, California, USA.
- Molecular Biology, Beckman Research Institute at City of Hope, Duarte, California, USA.
- Hematopoietic Cell Transplant, Beckman Research Institute at City of Hope, Duarte, California, USA.
- Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Correspondence to: Hua Yu1 e-mail: hyu@coh.org
