New therapeutic strategies are direly needed to treat pancreatic cancer. Over the last decade, tumor-ablation strategies, such as radiofrequency ablation, have emerged as promising therapeutic options. However, these strategies are associated with significant complications and treatment limitations. To circumvent these limitations, members of our research team developed a nonthermal tissue ablation modality, termed irreversible electroporation (IRE), for treating solid tumors. IRE delivers a series of low-energy, unipolar electric pulses through electrodes inserted directly into the tumor to produce structural defects in the target cell membrane and cell death. While the effectiveness of IRE in inducing targeted tumor ablation is well established, there is a paucity of data pertaining to immune system activation following IRE. Here, we hypothesize that IRE treatment will elicit robust proinflammatory cell death signaling and a strong anticancer immune response, ultimately leading to decreased disease burden. To evaluate this hypothesis, we utilized healthy pancreatic tissue, patient-derived xenograft (PDX) models, in vivo studies using immunocompetent mouse models, and studies in human patients. In healthy ex vivo pancreatic tissue, IRE induces predominately apoptotic cell death with limited proinflammatory effects. However, in ex vivo PDX tumors and in vivo murine pancreatic tumors, IRE induced voltage-dependent inflammatory cell death signaling, marked by the release of defined damage-associated molecular patterns (DAMPs). Mice treated with IRE exhibited 40% or more ablation of pancreatic tumors, significantly increased progression-free survival, and lower overall disease burden. IRE treatment also reduced local and systemic immunosuppressive cell populations, such as tumor-associated macrophages and T-regulatory cells, and increased proinflammatory signaling weeks after treatment. The increased proinflammatory signaling was, in part, associated with the generation of specific DAMPs and robust activation of the innate immune system. Additionally, we observed increased evidence of improved antigen presentation, altered immune checkpoint signaling pathways, and engagement of the adaptive immune system. Together, our data support a model whereby the unique cell death and tumor ablation following IRE treatment stimulate the local innate immune system, which shifts the tumor microenvironment from an anti-inflammatory state to a proinflammatory state. Likewise, the nonthermal nature of the ablation improves tumor antigen availability. Together, these mechanisms result in robust engagement of the adaptive immune system and improved systemic antitumor immune responses. We anticipate that IRE will be highly capable of improving conventional pancreatic cancer treatment strategies and complement emerging immunomodulatory approaches targeting primary tumors, metastatic lesions, and preventing recurrence.
This abstract is also being presented as Poster A11.
Citation Format: Rebecca M. Brock, Natalie Beitel-White, Melvin F. Lorenzo, Veronica M. Ringel-Scaia, Sheryl Coutermarsh-Ott, Navid Manuchehrabadi, Rafael V. Davalos, Irving C. Allen. Irreversible electroporation is an effective tumor-ablation strategy that induces immunologic cell death and promotes systemic antitumor immunity [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr PR8.