In vivo delivery of siRNA to immune cells by conjugation to a TLR9 agonist enhances antitumor immune responses.
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.
Kortylewski
Marcin
M
Department of Cancer Immunotherapeutics, Beckman Research Institute at City of Hope, Duarte, California, USA.
Swiderski
Piotr
P
Herrmann
Andreas
A
Wang
Lin
L
Kowolik
Claudia
C
Kujawski
Maciej
M
Lee
Heehyoung
H
Scuto
Anna
A
Liu
Yong
Y
Yang
Chunmei
C
Deng
Jiehui
J
Soifer
Harris S
HS
Raubitschek
Andrew
A
Forman
Stephen
S
Rossi
John J
JJ
Pardoll
Drew M
DM
Jove
Richard
R
Yu
Hua
H
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*
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