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

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.

• Authors: Hyunjoon Kim, Vidhi Khanna, Tamara A Kucaba, Wenqiu Zhang, Drishti Sehgal, David M Ferguson, Thomas S Griffith, Jayanth Panyam
• Journal: Molecular pharmaceutics (Mol Pharm) Vol. 17 Issue 6 Pg. 2109-2124 (06 01 2020) ISSN: 1543-8392 [Electronic] United States
• PMID: 32383885 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Toll-Like Receptor 7
• Toll-Like Receptor 8
• Imiquimod

Topics

• A549 Cells
• Animals
• Dendritic Cells (metabolism)
• Flow Cytometry
• Humans
• Imiquimod (chemistry)
• Immunotherapy (methods)
• Killer Cells, Natural (drug effects, metabolism)
• Leukocytes, Mononuclear (metabolism)
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Nanomedicine (methods)
• Nanoparticles (chemistry)
• Toll-Like Receptor 7 (agonists)
• Toll-Like Receptor 8 (agonists)