Polyethylenimine-based siRNA nanocomplexes reprogram tumor-associated dendritic cells via TLR5 to elicit therapeutic antitumor immunity. Academic Article uri icon

Overview

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.

authors

  • Cubillos-Ruiz, Juan R
  • Engle, Xavier
  • Scarlett, Uciane K
  • Martinez, Diana
  • Barber, Amorette
  • Elgueta, Raul
  • Wang, Li
  • Nesbeth, Yolanda
  • Durant, Yvon
  • Gewirtz, Andrew T
  • Sentman, Charles L
  • Kedl, Ross
  • Conejo-Garcia, Jose R

publication date

  • July 13, 2009

Research

keywords

  • Dendritic Cells
  • Nanoparticles
  • Ovarian Neoplasms
  • Polyethyleneimine
  • RNA, Small Interfering
  • Toll-Like Receptor 5

Identity

PubMed Central ID

  • PMC2719935

Scopus Document Identifier

  • 68849112640

Digital Object Identifier (DOI)

  • 10.1016/j.oraloncology.2005.07.013

PubMed ID

  • 19620771

Additional Document Info

volume

  • 119

issue

  • 8