Non-Thermal Histotripsy Ablation of Osteosarcoma Causes a Local Acute Immune Response

Abstract

Abstract While surgery, chemotherapy, and radiotherapy are available as treatments for osteosarcoma, there is only a 60% 5 year overall survival rate. To address this need, novel therapies are being developed and investigated. Histotripsy is a non-invasive, non-thermal focused-ultrasound ablation therapy that uses acoustic cavitation to mechanically lyse targeted cells. Recent evidence suggests that it is immunomodulatory, and can shift the tumor microenvironment to being more pro-inflammatory. However, given histotripsy’s mechanical mechanism, it is not established to be able to treat stronger tissues such as osteosarcomas at a dose that will allow for the preservation of immune stimulating molecules. In this study, mice with subcutaneous osteosarcoma DLM8 tumors were treated with histotripsy and acute changes to the local tumor immune response were analyzed 72 hours later. Using partial ablation to avoid off-target damage, a 40% average reduction in tumor size was achieved with targeted tissues being fully ablated. Through rtPCR, the levels of various cytokines associated with wound healing were significantly increased in the treated tumors following histotripsy treatment, with the greatest fold change observed in the concentrations for IL-6 and IL-13 over a given period of time. An increase in fold change for CD274, also known as PD-L1, was also observed, implicating the potential to pair histotripsy with checkpoint inhibitors for osteosarcoma therapy. The overall results of the study suggest that histotripsy is able to shift the tumor microenvironment following partial-ablation treatment. Thus, upon activation of the immune system, wound and tissue repair mechanisms are subsequently activated and responses are regulated.