Abstract
Stimulator of interferon genes (STING)-dependent signaling is requisite for effective anti-microbial and anti-tumor activity. STING signaling is commonly defective in cancer cells, which enables tumor cells to evade the immunosurveillance system. We evaluate here whether intrinsic STING signaling in such tumor cells could be reconstituted by creating recombinant herpes simplex viruses (rHSVs) that express components of the STING signaling pathway. We observe that rHSVs expressing STING and/or cGAS replicate inefficiently yet retain in vivo anti-tumor activity, independent of oncolytic activity requisite on the trans-activation of extrinsic STING signaling in phagocytes by engulfed microbial dsDNA species. Accordingly, the in vivo effects of virotherapy could be simulated by nanoparticles incorporating non-coding dsDNA species, which comparably elicit the trans-activation of phagocytes and augment the efficacy of established cancer treatments including checkpoint inhibition and radiation therapy. Our results help elucidate mechanisms of virotherapeutic anti-tumor activity as well as provide alternate strategies to treat cancer.
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•HSV virotherapy entails the transactivation of STING in APCs via microbial nucleic acid•Nanoparticles with dsDNA species can mimic HSV virotherapy, inducing anti-tumor CTLs•STING signaling in APCs entails the co-phagocytosis of nano-STAVs with dying tumor cells•Nano-STAVs synergize with IFN and/or radiation and augment anti-PD1 therapy
Delaunay et al. demonstrate that generating non-replicating nanoparticles that contain only non-coding dsDNA species is sufficient to promote the generation of anti-tumor cytotoxic T cells following intratumoral inoculation, and they can synergize with as well as augment the therapeutic effects of established anti-cancer treatments.