title: In vivo delivery of siRNA to immune cells by conjugation to a TLR9 agonist enhances antitumor immune responses.
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.
authors.affiliation: Department of Cancer Immunotherapeutics, Beckman Research Institute at City of Hope, Duarte, California, USA.
authors.forename: Marcin
authors.initials: M
authors.lastname: Kortylewski
authors.forename: Piotr
authors.initials: P
authors.lastname: Swiderski
authors.forename: Andreas
authors.initials: A
authors.lastname: Herrmann
authors.forename: Lin
authors.initials: L
authors.lastname: Wang
authors.forename: Claudia
authors.initials: C
authors.lastname: Kowolik
authors.forename: Maciej
authors.initials: M
authors.lastname: Kujawski
authors.forename: Heehyoung
authors.initials: H
authors.lastname: Lee
authors.forename: Anna
authors.initials: A
authors.lastname: Scuto
authors.forename: Yong
authors.initials: Y
authors.lastname: Liu
authors.forename: Chunmei
authors.initials: C
authors.lastname: Yang
authors.forename: Jiehui
authors.initials: J
authors.lastname: Deng
authors.forename: Harris S
authors.initials: HS
authors.lastname: Soifer
authors.forename: Andrew
authors.initials: A
authors.lastname: Raubitschek
authors.forename: Stephen
authors.initials: S
authors.lastname: Forman
authors.forename: John J
authors.initials: JJ
authors.lastname: Rossi
authors.forename: Drew M
authors.initials: DM
authors.lastname: Pardoll
authors.forename: Richard
authors.initials: R
authors.lastname: Jove
authors.forename: Hua
authors.initials: H
authors.lastname: Yu
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001402:B-Lymphocytes / Q000502:physiology; D045744:Cell Line, Tumor; D018925:Chemokines / Q000378:metabolism; D004274:DNA, Recombinant / Q000235:genetics; D003713:Dendritic Cells / Q000502:physiology; D005434:Flow Cytometry; D020868:Gene Silencing; D018014:Gene Transfer Techniques; D007113:Immunity, Innate / Q000187:drug effects; D008264:Macrophages / Q000502:physiology; D051379:Mice; D022423:Myeloid Cells / Q000502:physiology; D009369:Neoplasms / Q000235:genetics / Q000276:immunology; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage* / Q000737:chemistry / Q000235:genetics / Q000493:pharmacokinetics; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000737:chemistry / Q000235:genetics / Q000493:pharmacokinetics; D050796:STAT3 Transcription Factor / Q000235:genetics*; D051217:Toll-Like Receptor 9 / Q000819:agonists*
chemical_list: D018925:Chemokines; D004274:DNA, Recombinant; D009838:Oligodeoxyribonucleotides; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9