Modulating the Cell Death Immune Response for Electroporation Treatments

Abstract

Irreversible electroporation (IRE) is a minimally invasive ablation technique that compromises integrity of the cell membrane through the application of short duration, high voltage electric pulses to induce cell death. Adverse effects of IRE such as muscle contractions are reduced with higher frequency biphasic pulsing, commonly known as high-frequency irreversible electroporation (H-FIRE). IRE and H-FIRE treatments have shown to increase immune activation through the induction of both immediate and delayed cell death, indicated by the release of damage-associated molecular pathways, antigens, and proteins. In this study, we demonstrated that specific modes of cell death can be elicited by modifying the applied pulse width and electric field strength of various waveforms. Several assays were performed on a human glioblastoma cell line, seeded onto a 2D monolayer for electroporation treatments. Cleavage of Caspase 3/7 and Caspase 1, well-known indicators of apoptosis and pyroptosis, respectively, was quantified. Our results indicate that apoptotic activity was increased for shorter pulse widths and stronger electric fields, whereas pyroptotic activity displayed opposite trends being significantly dominant with longer pulse widths at lower applied electric fields. When clinically applied, the activation of specific cell death mechanisms can allow for controlling the extent of an electroporation-mediated immune response and subsequently improved overall patient survival. With this information, we could use an electrode array to spatially manipulate the elicited immune response for patient-specific treatments.

Keywords: Caspase 1; Caspase 3/7; apoptosis; cell death mechanism; inflammatory; multielectrode array; pyroptosis.