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EBioMedicine. 2019 Jun;44:112-125. doi: 10.1016/j.ebiom.2019.05.036. Epub 2019 May 23.

High-frequency irreversible electroporation is an effective tumor ablation strategy that induces immunologic cell death and promotes systemic anti-tumor immunity.

Author information

1
Graduate Program in Translational Biology, Medicine, and Health, Virginia Tech, Blacksburg, VA, USA; Department of Biomedical Sciences and Pathobiology, Virginia Tech, Virginia-Maryland College of Veterinary Medicine, Blacksburg, VA, USA.
2
Bioelectromechanical Systems Laboratory, Department of Biomedical Engineering and Mechanics, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA; Department of Electrical and Computer Engineering, Virginia Tech, Blacksburg, VA, USA.
3
Bioelectromechanical Systems Laboratory, Department of Biomedical Engineering and Mechanics, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA; Virginia Tech - Wake Forest University, Virginia Tech, School of Biomedical Engineering & Sciences, Blacksburg, VA, USA.
4
Department of Biomedical Sciences and Pathobiology, Virginia Tech, Virginia-Maryland College of Veterinary Medicine, Blacksburg, VA, USA.
5
Department of Biomedical Sciences and Pathobiology, Virginia Tech, Virginia-Maryland College of Veterinary Medicine, Blacksburg, VA, USA; Department of Basic Science Education, Virginia Tech Carilion School of Medicine, Roanoke, VA, USA.
6
Virginia Tech - Wake Forest University, Virginia Tech, School of Biomedical Engineering & Sciences, Blacksburg, VA, USA; Center for Engineered Health, Virginia Tech, Institute for Critical Technology and Applied Science, Blacksburg, VA, USA.
7
Center for Engineered Health, Virginia Tech, Institute for Critical Technology and Applied Science, Blacksburg, VA, USA; Department of Small Animal Clinical Sciences, Virginia-Maryland College of Veterinary Medicine, Blacksburg, VA, USA.
8
Graduate Program in Translational Biology, Medicine, and Health, Virginia Tech, Blacksburg, VA, USA; Department of Biomedical Sciences and Pathobiology, Virginia Tech, Virginia-Maryland College of Veterinary Medicine, Blacksburg, VA, USA; Department of Internal Medicine, Virginia Tech Carilion School of Medicine, Roanoke, VA, USA; Center for Engineered Health, Virginia Tech, Institute for Critical Technology and Applied Science, Blacksburg, VA, USA; Virginia Tech, Fralin Biomedical Research Institute at Virginia Tech Carilion, Roanoke, VA, USA.
9
Graduate Program in Translational Biology, Medicine, and Health, Virginia Tech, Blacksburg, VA, USA; Bioelectromechanical Systems Laboratory, Department of Biomedical Engineering and Mechanics, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA; Virginia Tech - Wake Forest University, Virginia Tech, School of Biomedical Engineering & Sciences, Blacksburg, VA, USA; Department of Basic Science Education, Virginia Tech Carilion School of Medicine, Roanoke, VA, USA; Center for Engineered Health, Virginia Tech, Institute for Critical Technology and Applied Science, Blacksburg, VA, USA.
10
Graduate Program in Translational Biology, Medicine, and Health, Virginia Tech, Blacksburg, VA, USA; Department of Biomedical Sciences and Pathobiology, Virginia Tech, Virginia-Maryland College of Veterinary Medicine, Blacksburg, VA, USA; Department of Basic Science Education, Virginia Tech Carilion School of Medicine, Roanoke, VA, USA; Center for Engineered Health, Virginia Tech, Institute for Critical Technology and Applied Science, Blacksburg, VA, USA. Electronic address: icallen@vt.edu.

Abstract

BACKGROUND:

Despite promising treatments for breast cancer, mortality rates remain high and treatments for metastatic disease are limited. High-frequency irreversible electroporation (H-FIRE) is a novel tumor ablation technique that utilizes high-frequency bipolar electric pulses to destabilize cancer cell membranes and induce cell death. However, there is currently a paucity of data pertaining to immune system activation following H-FIRE and other electroporation based tumor ablation techniques.

METHODS:

Here, we utilized the mouse 4T1 mammary tumor model to evaluate H-FIRE treatment parameters on cancer progression and immune system activation in vitro and in vivo.

FINDINGS:

H-FIRE effectively ablates the primary tumor and induces a pro-inflammatory shift in the tumor microenvironment. We further show that local treatment with H-FIRE significantly reduces 4T1 metastases. H-FIRE kills 4T1 cells through non-thermal mechanisms associated with necrosis and pyroptosis resulting in damage associated molecular pattern signaling in vitro and in vivo. Our data indicate that the level of tumor ablation correlates with increased activation of cellular immunity. Likewise, we show that the decrease in metastatic lesions is dependent on the intact immune system and H-FIRE generates 4T1 neoantigens that engage the adaptive immune system to significantly attenuate tumor progression.

INTERPRETATION:

Cell death and tumor ablation following H-FIRE treatment activates the local innate immune system, which shifts the tumor microenvironment from an anti-inflammatory state to a pro-inflammatory state. The non-thermal damage to the cancer cells and increased innate immune system stimulation improves antigen presentation, resulting in the engagement of the adaptive immune system and improved systemic anti-tumor immunity.

KEYWORDS:

Breast cancer; IRE; Metastasis; Pyroptosis; Tumor microenvironment

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