LAUSR

Activated natural killer (NK) cells can kill malignant tumor cells via granule exocytosis and secretion of IFN-ɣ, a key regulator of TH1 response. Thus, mobilization of NK cells can augment cancer immunotherapy, particularly that mediated through antibody-dependent cellular cytotoxicity (ADCC). Stimulation of toll-like receptor (TLR)7/8 activity in dendritic cells is known to promote pro-inflammatory cytokine secretion and co-stimulatory molecule upregulation, both of which can potentiate NK cell activation. However, currently available TLR7 and 7/8 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 co-stimulatory molecule expression on dendritic cells and stronger pro-inflammatory cytokine response was observed with 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 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 anti-tumor efficacy of cetuximab and an anti-HER2/neu antibody in mouse tumor models. Here, we show that pH responsive NPs encapsulating TLR7/8 agonist could be used as a potent immunostimulatory adjuvant for antibody-based cancer immunotherapy by promoting NK cell activation.