Eliciting STING pathway activation and a type 1 interferon response in bladder cancer cells with double stranded DNA delivered by lambda phage based nanoparticles 3231

Abstract Description Bladder cancer is the sixth most common cause of tumor formation in the United States and the thirteenth leading cause of cancer-related deaths worldwide. Current therapies often rely on the bladders’ immune responses or introducing live attenuated vaccines, such as Bacillus Calmette–Guérin (BCG). These immune based strategies can be effective but with a high rate of recurrence and due to non-responding patients there is a need for additional treatment options. In this study, we targeted the stimulator of interferon genes (STING) pathway to elicit a type 1 interferon response in bladder cancer cells by delivering a 45bp duplexed interferon stimulating DNA strand. To accomplish this, we developed a nanoparticle delivery system utilizing the bacteriophage lambda capsid. We conjugated the 45bp DNA strand to a decoration protein on the lambda phage capsid for intracellular delivery along with Cetuximab for targeting bladder cancer cells as well as fluorescein for imaging. We were able to demonstrate uptake of the lambda phage nanoparticles into MB49 mouse bladder cancer cells with a 5% and 10% Cetuximab density using confocal microscopy. Importantly, there was a significant increase in IFN-β of 20-40 pg/mL with treatment of DNA decorated phage particles as well as a significant fold change increase of IFN-β gene expression compared to DNA alone and 2’3’-cGAMP. Overall, Lamba phage particles decorated with interferon stimulatory DNA elicit an anti-tumor immune response. Funding Sources Supported by DOD CA190078 Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)