Irreversible electroporation stimulates a pro-inflammatory tumor microenvironment in pancreatic cancer

Abstract Pancreatic cancer is a major cancer with a survival rate of only 6% due to late diagnosis and the aggressiveness of the malignancy. There is also a severe lack of viable treatment options due to the localization of the primary tumor near major blood vessels and bile ducts as well as the highly immunosuppressive nature and metastatic potential of pancreatic cancer. New ablative techniques for pancreatic tumors are being developed; however most are thermal and can cause damage to the delicate surrounding structures. Non-thermal irreversible electroporation (IRE) uses short, high frequency electrical pulses to permeabilize cancer cell membranes and illicit cell death. IRE has shown promising results in clinical trials of late-stage, locally advanced cases. Here we utilize several models of pancreatic cancer in vitro, ex vivo, and in vivo to determine the effect of IRE on cell death pathways, cancer pathways, and immune signaling. IRE elicits pro-inflammatory cell death via necrosis and pyroptosis in immunocompetent murine and human patient-derived xenograft models. This pro-inflammatory environment can stimulate immune cell infiltration to the tumor site, halting tumor progression. Moreover, a non-thermal ablative approach also preserves cancer cell antigens that can lead to better immunosurveillance against reoccurrence and metastatic lesions. With the advent of these new techniques, the impact of such technologies to the tumor microenvironment and immune system need to be assessed to determine their clinical application. IRE is proving to be a safe and effective treatment for pancreatic cancer as it not only ablates the primary tumor site but also stimulates the immune system to recognize and combat the tumor throughout the body.