In vivo delivery of siRNA to immune cells by conjugation to a TLR9 agonist enhances antitumor immune responses

Open Access
Publisher Website
Google Scholar
Abstract
Tumors generate microenvironments that actively suppress the body's anti-tumor immune response. Kortylewski et al. restore immunity by delivering an siRNA against Stat3, a regulator of immune suppression, to myeloid and B cells using a CpG oligonucleotide that targets toll-like receptor 9. 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.