title: Inhibition of lung metastasis by chemokine CCL17-mediated in vivo silencing of genes in CCR4+ Tregs.
abstract: Despite significant attractiveness of antisense oligonucleotide/RNAi technology, its clinical application has been precluded by a lack of methods for targeted delivery and transduction of primary immune cells in vivo. Here, we devised a chemokine CCL17-based strategy (TARC-arp) that transiently silences expression of genes in immune cells by delivering inhibitory oligonucleotides through their chemokine receptors. In modeling studies using mice with established 4T1.2 breast cancer, we show that IL10 produced by CCR4 cells, in particular FoxP3 regulatory T cells (Tregs), plays an important role in lung metastasis. As such, TARC-arp-mediated silencing of IL10 or FoxP3 in CCR4 Tregs is sufficient to block lung metastasis. Thus, we provide a simple solution that circumvents the problems of RNAi use in vivo, indicating that a disease outcome can be successfully controlled by delivering inhibitory oligonucleotides with chemokines to inactivate a selective subset of immune cells.
authors.affiliation: Immunotherapeutics Section, Laboratory of Molecular Biology and Immunology, National Institute on Aging, Baltimore, MD 21224, USA. biragyna@mail.nih.gov
authors.forename: Arya
authors.initials: A
authors.lastname: Biragyn
authors.forename: Monica
authors.initials: M
authors.lastname: Bodogai
authors.forename: Purevdorj B
authors.initials: PB
authors.lastname: Olkhanud
authors.forename: Sinan R
authors.initials: SR
authors.lastname: Denny-Brown
authors.forename: Nitin
authors.initials: N
authors.lastname: Puri
authors.forename: Koichi
authors.initials: K
authors.lastname: Ayukawa
authors.forename: Shiro
authors.initials: S
authors.lastname: Kanegasaki
authors.forename: Cory M
authors.initials: CM
authors.lastname: Hogaboam
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Wejksza
authors.forename: Catalina
authors.initials: C
authors.lastname: Lee-Chang
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D054414:Chemokine CCL17 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism / Q000556:secondary; D016246:Lymphocytes, Tumor-Infiltrating; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage; D054398:Receptors, CCR4 / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism*
chemical_list: D054414:Chemokine CCL17; D035683:MicroRNAs; D016376:Oligonucleotides, Antisense; D054398:Receptors, CCR4; D011993:Recombinant Fusion Proteins; D016753:Interleukin-10