TLR7/8 Agonist-Loaded Nanoparticles Augment NK Cell-Mediated Antibody-Based Cancer Immunotherapy

Hyunjoon Kim, Vidhi Khanna, Tamara A. Kucaba, Wenqiu Zhang, Drishti Sehgal, David M. Ferguson, Thomas S. Griffith, Jayanth Panyam

Research output: Contribution to journalArticle

Abstract

Activated natural killer (NK) cells can kill malignant tumor cells via granule exocytosis and secretion of IFN-γ, a key regulator of the TH1 response. Thus, mobilization of NK cells can augment cancer immunotherapy, particularly when mediated through antibody-dependent cellular cytotoxicity (ADCC). Stimulation of toll-like receptor (TLR)7/8 activity in dendritic cells promotes pro-inflammatory cytokine secretion and costimulatory molecule upregulation, both of which can potentiate NK cell activation. However, currently available TLR7/8 agonists exhibit unfavorable pharmacokinetics, limiting their in vivo efficacy. To enable efficient delivery to antigen-presenting cells, we encapsulated a novel imidazoquinoline-based TLR7/8 agonist in pH-responsive polymeric NPs. Enhanced costimulatory molecule expression on dendritic cells and a stronger pro-inflammatory cytokine response were observed with a NP-encapsulated agonist, compared to that with the soluble form. Treatment with NP-encapsulated agonists resulted in stronger in vivo cytotoxicity and prolonged activation of NK cells compared to that with a soluble agonist. In addition, TLR7/8 agonist-loaded NPs potentiated stronger NK cell degranulation, which resulted in enhanced in vitro and in vivo ADCC mediated by the epidermal growth factor receptor-targeting antibody cetuximab. TLR7/8 agonist-loaded NP treatment significantly enhanced the antitumor efficacy of cetuximab and an anti-HER2/neu antibody in mouse tumor models. Collectively, our data show that a pH-responsive NP-encapsulating TLR7/8 agonist could be used as a potent immunostimulatory adjuvant for antibody-based cancer immunotherapy by promoting NK cell activation.

Original languageEnglish (US)
Pages (from-to)2109-2124
Number of pages16
JournalMolecular pharmaceutics
Volume17
Issue number6
DOIs
StatePublished - Jun 1 2020

Keywords

  • ADCC
  • NK cell
  • TLR7/8 agonist
  • cancer immunotherapy
  • nanomedicine

PubMed: MeSH publication types

  • Journal Article

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