Histotripsy Ablation Alters the Tumor Microenvironment and Promotes Immune System Activation in a Subcutaneous Model of Pancreatic Cancer

Abstract

Pancreatic cancer is a significant cause of cancerrelated deaths in the United States with an abysmal 5-year overall survival rate that is under 9%. Reasons for this mortality include the lack of late-stage treatment options and the immunosuppressive tumor microenvironment. Histotripsy is an ultrasound-guided, non-invasive, non-thermal tumor ablation therapy that mechanically lyses targeted cells. To study the effects of histotripsy on pancreatic cancer, we utilized an in vitro model of pancreatic adenocarcinoma and compared the release of potential antigens following histotripsy treatment to other ablation modalities. Histotripsy was found to release immune-stimulating molecules at magnitudes similar to other non-thermal ablation modalities and superior to thermal ablation modalities, which corresponded to increased innate immune system activation in vivo. In subsequent in vivo studies, murine Pan02 tumors were grown in mice and treated with histotripsy. Flow cytometry and rtPCR were used to determine changes in the tumor microenvironment over time compared to untreated animals. In mice with pancreatic tumors, we observed significantly increased tumor-progression-free and general survival, with increased activation of the innate immune system 24 hours post-treatment and decreased tumor-associated immune cell populations within 14 days of treatment. This study demonstrates the feasibility of using histotripsy for pancreatic cancer ablation and provides mechanistic insight into the initial innate immune system activation following treatment. Further work is needed to establish the mechanisms behind the immunomodulation of the tumor microenvironment and immune effects.

Immunological Effects of Histotripsy for Cancer Therapy

“…In mouse models, histotripsy ablation of hepatic, renal, neuroblastoma, melanoma, and pancreatic tumors has resulted in significantly increased survival (22,(110)(111)(112)(113). In addition to debulking tumors, recent evidence has suggested that histotripsy has the capability to induce a systemic immune response, as evidenced by the attenuation of metastasis and an improvement in local and distant disease with combination immunotherapy (22,114,115).…”

Latest Advances in the Use of Therapeutic Focused Ultrasound in the Treatment of Pancreatic Cancer

“…No changes in immune cells in the microenvironment of the tumours were seen 24 h and 7 days after histotripsy, and then a decrease in macrophages (percentage of CD45 + cells) and regulatory T cells (percentage of total cells) and an increase in DC (as a percentage of CD45 + cells) was seen 14 days after histotripsy treatments. The same authors also showed the release of DAMPS, including HMGB1 release, after the treatment of the Pan02 cells in vitro with the same histotripsy parameters (parameters: f = 1 MHz, 8 elements, f-number = 0.68, focus = 0.98 × 0.93 × 3.9 mm, pulses < 2 cycles, prf = 250 Hz) [204]. Sonodynamic therapy has also shown pro-immune effects in preclinical models of pancreatic cancer.…”

Pancreatic Ductal Adenocarcinoma: Current and Emerging Therapeutic Uses of Focused Ultrasound

“…More anecdotally, two case studies reported abscopal effects following thermal ablation [ 111 , 112 ]. Preclinical data regarding immune effects in animal models of pancreatic cancer have recently been published [ 100 , 101 , 113 , 114 ]. The interested reader can refer to the detailed comprehensive review of those studies recently provided by Mouratidis and ter Haar [ 115 ].…”