Histotripsy initiates local and systemic immunological response and reduces tumor burden in breast cancer

Abstract Histotripsy is an emerging, non-invasive, and non-thermal tumor ablation method that has been shown to ablate tissues with millimeter precision guided by real-time ultrasound imaging feedback. Histotripsy ablates tissues by focusing high pressure ultrasound pulses to create cavitation, liquefying tissue. By utilizing this mechanism, preliminary data has suggested that Histotripsy could be used to both ablate a primary tumor and to stimulate the immune system to treat metastatic disease. However, there has not been work done to date on investigating the interactions of the immune system with Histotripsy. For the current work, we hypothesized Histotripsy treatment of a 4T1 tumor in a murine model would stimulate local and systemic immune system responses with an improvement on disease burden. Here, we show that Histotripsy was able to reduce the size of the treated tumor, number of metastases, and change the cytokine profiles. Treated tumors had an average of 15% reduction in volume in 24hrs following treatment and showed increases in necrosis and innate immune cell infiltration. Analysis of early response revealed increased pro-inflammatory cytokines, correlating with increased anti-tumor microenvironments. At a long term follow up, Histotripsy decreased disease burden through primary tumor size and metastasis number. These results demonstrate Histotripsy can stimulate an immunological effect with the increased anti-tumor microenvironment in the treated area one day after treatment, and overall disease morbidity in the long term. Histotripsy has promise as an immunomodulating tumor ablation method for breast cancer, and, once established, has the potential to be utilized in different tumor types as well.