The Stimulator of Interferon Genes (STING) pathway is implicated in the innate immune response and is important in both oncogenesis and cancer treatment. Specifically, activation of the cytosolic DNA sensor STING in antigen presenting cells (APCs) induces a type I interferon response and cytokine production that facilitates anti-tumor immune therapy. However, use of STING agonists (STINGa) as a cancer therapeutic has been limited by unfavorable pharmacological properties and targeting inefficiency due to rapid clearance and limited uptake into the cytosol. Exosomes, a class of extracellular vesicles shed by all cells, are under consideration for their use as effective carriers of drugs owing to their innate ability to be taken up by cells and their biocompatibility for optimal drug biodistribution.
Researchers from the MD Anderson Cancer Center have engineered exosomes to deliver the STING agonist cyclic GMP-AMP (iExoSTINGa), to exploit their favorable pharmacokinetics and pharmacodynamics. Selective targeting of the STING pathway in APCs with iExoSTINGa was associated with superior potency compared to STINGa alone in suppressing B16F10 tumor growth. Moreover, iExoSTINGa showed superior uptake of STINGa into dendritic cells compared to STINGa alone, which led to increased accumulation of activated CD8+ T-cells and an anti-tumor immune response. This study highlights the potential of exosomes in general, and iExoSTINGa specifically, in enhancing cancer therapy outcomes.
Characterization of iExoSTINGa
A. Schematic representation of iExoSTINGa generation. B. Concentration and size distribution of purified HEK293T exosomes and iExoSTINGa. C. Mode particle diameter of purified HEK293T exosomes and iExoSTINGa, n=3 independent experiments. Mann-Whitney test performed. D. Representative FACS histograms for CD9, CD63 and CD81 on HEK293T exosomes and iExoSTINGa. E. Plate reader-based quantification of fluorescein-STINGa in exosomes in the presence of 200 μM folic acid or 100 mM glutamine. n=3-7 independent experiments. One-way ANOVA with Bonferroni’s multiple comparison test performed. F. Plate reader-based quantification of fluorescein-STINGa in exosomes in the presence of Proteinase K. n=5-6 independent experiments. Mann-Whitney test performed. G-H. Representative FACS plots (H) and quantification of fluorescein labeled STINGa (G) in the listed samples. n=3 independent experiments. One-way ANOVA with Bonferroni’s multiple comparison test performed. H. Representative FACS plots and quantification of the percent of fluorescein-STINGa positive BMDCs in the indicated treatment groups. I. Relative gene expression (fold change relative to untreated cells) of Ifnb1 (left panel), Cxcl10 (center panel), and Il6 (right panel) in wild type (WT) and STING KO BMDCs treated with varying concentrations of STINGa or iExoSTINGa (1×1011 HEK293T exosomes loaded with varying amounts of STINGa). One-way ANOVA with Bonferroni’s multiple comparison test performed. The data are presented as the mean ± SEM. * P < 0.05, ** P < 0.01, *** P < 0.001, **** P < 0.0001, ns: not significant.