Histotripsy ablation stimulates the innate immune system and modulates anti-tumor immunity in pancreatic cancer

Abstract With an overall 5-year survival rate of less than 9%, pancreatic cancer is a substantial cause of cancer related death in the United States. This high mortality has been associated with the immunosuppressive tumor microenvironment (TME) and the shortage of effective late-stage therapeutic options. Histotripsy is a non-thermal, non-ionizing, non-invasive cancer ablation modality that rapidly lyses targeted cells. To investigate how histotripsy can change the pancreatic TME, a Pan02 cell culture model of pancreatic adenocarcinoma was employed to determine the neoantigen release following histotripsy treatment and other standard ablation modalities. Histotripsy was found to release potential neoantigens at a level similar to other non-thermal ablations and superior to thermal ablation, which paralleled the increased innate immune system activation in vivo. For in vivo studies, subcutaneous Pan02 tumors in mice were treated with histotripsy. To monitor changes in the TME after treatment, rtPCR and flow cytometry were used and compared to untreated animals. Progression-free and overall survival were significantly improved with histotripsy treatment. Within 24 hours of treatment there was increased activation of the innate immune system and by 14 days there were decreased tumor-associated immune cell populations. This work illustrates the feasibility of using histotripsy to treat pancreatic cancer and shift the TME as well as providing mechanistic understanding into the activation of the innate immune system post-treatment. Future studies are needed to establish the mechanism of immunomodulation of the TME and the extent of potential systemic effects.