Reprogramming tumor-associated dendritic cells in vivo using miRNA mimetics triggers protective immunity against ovarian cancer.
Modulating the activity of miRNAs provides opportunities for novel cancer interventions. However, low bioavailability and poor cellular uptake are major challenges for delivering miRNA mimetics specifically to tumor cells. Here, we took advantage of the spontaneous enhanced endocytic activity of ovarian cancer-associated dendritic cells (DC) to selectively supplement the immunostimulatory miRNA miR-155. In vivo processing of nanoparticles carrying oligonucleotide duplexes mimicking the bulged structure of endogenous pre-miRNA (but not siRNA-like oligonucleotides) dramatically augmented miR-155 activity without saturating the RNA-induced silencing complex. Endogenous processing of synthetic miR-155 favored Ago2 and, to a lesser extent, Ago4 loading, resulting in genome-wide transcriptional changes that included silencing of multiple immunosuppressive mediators. Correspondingly, tumor-infiltrating DCs were transformed from immunosuppressive to highly immunostimulatory cells capable of triggering potent antitumor responses that abrogated the progression of established ovarian cancers. Our results show both the feasibility and therapeutic potential of supplementing/replenishing miRNAs in vivo using nonviral approaches to boost protective immunity against lethal tumors. Thus, we provide a platform, an optimized design, and a mechanistic rationale for the clinical testing of nonviral miRNA mimetics.
Department of Microbiology and Immunology, Dartmouth Medical School, Lebanon, New Hampshire, USA.
Juan R
JR
Cubillos-Ruiz
Jason R
JR
Baird
Amelia J
AJ
Tesone
Melanie R
MR
Rutkowski
Uciane K
UK
Scarlett
Ana L
AL
Camposeco-Jacobs
Jorge
J
Anadon-Arnillas
Noah M
NM
Harwood
Murray
M
Korc
Steven N
SN
Fiering
Lorenzo F
LF
Sempere
Jose R
JR
Conejo-Garcia
D000818:Animals; D060565:Argonaute Proteins / Q000008:administration & dosage; D019013:CD40 Antigens / Q000502:physiology; D003713:Dendritic Cells / Q000276:immunology*; D004705:Endocytosis; D005260:Female; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000502:physiology*; D010051:Ovarian Neoplasms / Q000276:immunology*; D034743:RNA-Induced Silencing Complex; D059467:Transcriptome; D059016:Tumor Microenvironment
C526735:Ago2 protein, mouse; D060565:Argonaute Proteins; D019013:CD40 Antigens; D035683:MicroRNAs; C532623:Mirn155 microRNA, mouse; D034743:RNA-Induced Silencing Complex