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Polyethylenimine-Based siRNA Nanocomplexes Reprogram Tumor-Associated Dendritic Cells via TLR5 to Elicit Therapeutic Antitumor Immunity
The Journal of Clinical Investigation
  • Juan R. Cubillos-Ruiz, Dartmouth Medical School
  • Xavier Engle, Dartmouth Medical School
  • Uciane K. Scarlett, Dartmouth Medical School
  • Diana Martinez, Dartmouth Medical School
  • Amorette Barber, Longwood University
  • Raul Elgueta, Dartmouth Medical School
  • Li Wang, Dartmouth Medical School
  • Yolanda Nesbeth, Dartmouth Medical School
  • Yvon Durant, Nanostructured Polymers Research Center
  • Andrew T. Gewirtz, Emory University
  • Charles L. Sentman, Dartmouth Medical School
  • Ross Kedl, University of Colorado at Denver and Health Sciences Center
  • Jose R. Conejo-Garcia, Dartmouth Medical School
Document Type
Article
Publication Date
8-1-2009
Abstract

The success of clinically relevant immunotherapies requires reversing tumor-induced immunosuppression. Here we demonstrated that linear polyethylenimine-based (PEI-based) nanoparticles encapsulating siRNA were preferentially and avidly engulfed by regulatory DCs expressing CD11c and programmed cell death 1–ligand 1 (PD-L1) at ovarian cancer locations in mice. PEI-siRNA uptake transformed these DCs from immunosuppressive cells to efficient antigen-presenting cells that activated tumor-reactive lymphocytes and exerted direct tumoricidal activity, both in vivo and in situ. PEI triggered robust and selective TLR5 activation in vitro and elicited the production of hallmark TLR5-inducible cytokines in WT mice, but not in Tlr5–/– littermates. Thus, PEI is a TLR5 agonist that, to our knowledge, was not previously recognized. In addition, PEI-complexed nontargeting siRNA oligonucleotides stimulated TLR3 and TLR7. The nonspecific activation of multiple TLRs (specifically, TLR5 and TLR7) reversed the tolerogenic phenotype of human and mouse ovarian tumor–associated DCs. In ovarian carcinoma–bearing mice, this induced T cell–mediated tumor regression and prolonged survival in a manner dependent upon myeloid differentiation primary response gene 88 (MyD88; i.e., independent of TLR3). Furthermore, gene-specific siRNA-PEI nanocomplexes that silenced immunosuppressive molecules on mouse tumor-associated DCs elicited discernibly superior antitumor immunity and enhanced therapeutic effects compared with nontargeting siRNA-PEI nanocomplexes. Our results demonstrate that the intrinsic TLR5 and TLR7 stimulation of siRNA-PEI nanoparticles synergizes with the gene-specific silencing activity of siRNA to transform tumor-infiltrating regulatory DCs into DCs capable of promoting therapeutic antitumor immunity.

DOI
10.1172/JCI37716
Version
Publisher's PDF
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Comments

© 2009 American Society for Clinical Investigation.

Original Citation

J. Clin. Invest.119:22312244 (2009). doi:10.1172/JCI37716.

Citation Information
Juan R. Cubillos-Ruiz, Xavier Engle, Uciane K. Scarlett, Diana Martinez, et al.. "Polyethylenimine-Based siRNA Nanocomplexes Reprogram Tumor-Associated Dendritic Cells via TLR5 to Elicit Therapeutic Antitumor Immunity" The Journal of Clinical Investigation Vol. 119 Iss. 8 (2009) p. 2231 - 2244
Available at: http://works.bepress.com/amorette_barber/1/