Irreversible electroporation enhances immunotherapeutic effect in the off-target tumor in a murine model of orthotopic HCC.

Irreversible electroporation (IRE) has been postulated to have an off-target effect on lesions not in the tumor-ablative field, possibly through heightened immunologic response. In this study, we evaluated whether combination IRE and immunotherapy would lead to increased tumor necrosis and T cell recruitment to both the treated tumors and tumors outside the local ablative field. An cell-IRE model was established to evaluate the ability of T lymphocytes (EL4 cell and HH cells) migration in response to Hepatocellular carcinoma (HCC) cells (Hepa1-6 and HepG2) with IRE treatment. An orthotopic HCC mouse model was established by implantation of 1mm^3 sections of Hepa1-6 tumor tissues into the right and left lobes of the liver. The Hepa1-6 cells and HepG2 cells with IRE treatment increased the migration ability of EL4 cell and HH cells, specifically when they were pretreated with immunotherapeutic agents in vitro. In the orthotopic HCC mouse model, IRE+immunotherapy treatment enhanced the necrosis and subpopulation of infiltrated CD8 positive cells, but attenuated the tumor associated inflammatory cells in both IRE target tumor tissues and IRE off-target tumor tissues from the mice with 4 weeks of immunotherapy following IRE. This study provided the evidence that combination of IRE and immunotherapy enhances tumor necrosis and immune responses, not only in the IRE-treated tumor but also in the off-target tumor.