Irreversible electroporation stimulates a pro-inflammatory tumor microenvironment that facilitate antigen presentation in pancreatic cancer

Abstract

Abstract Pancreatic cancer is now the third leading cause of cancer-related death and is projected to turn out to be the second by 2030. Pancreatic cancer is often late-diagnosed with few treatment options with extremely low survival rates. Surgical candidacy is only 15% of total diagnosed patients. Irreversible electroporation (IRE), a novel form of tumor non-thermal ablation applies high-voltage microsecond pulses to permeabilize the cell membrane that is irreversible and leads to apoptotic cell death. IRE has had strong success in clinical trials for pancreatic cancer patients. Nevertheless, little is known on the effect of IRE beyond the initiation of cell death in the tumor tissue. We hypothesize that IRE can induce a pro-inflammatory type of cell death in pancreatic cancer that can promote inflammation and anti-tumor immune system responses. We have used in vitro, ex vivo, and immunocompetent in vivo murine models to investigate alterations to pancreatic cancer and its microenvironment. Our findings reveal programmed necrotic cell death, promotion of pro-inflammatory cytokine production, and shifts in immune cell populations from a pro-tumor (such as MDSCs and T regulatory cells) to a proinflammatory types containing cytotoxic lymphocytes and neutrophils after IRE treatment. Progression-free survival was significantly longer for the treated mice. Intriguingly, IRE treatment increases IFNγ signaling and generates viable antigens for presentation to the adaptive immune system but also promotes PD-L1 expression which in turn causes immunological stalemate. Our results suggest possible therapeutic targets for use in combination with IRE, such as gemcitabine or PD-1/PD-L1 inhibitors, to improve patient survival.