IFNγ mediated PD-L1 expression mitigate the immunomodulatory effect of irreversible electroporation on pancreatic cancer

Abstract

Abstract Pancreatic cancer is one of the deadliest diagnoses leaving patients with few therapeutic options. Irreversible electroporation (IRE), a novel non-thermal ablation system, utilizes very short, high voltage electrical pulses to form micropores in cell membranes and stimulate cell death. IRE has been tested in human clinical trials for pancreatic cancer treatment with a significant improvement in progression-free survival, but not much is understood about the immunomodulatory effects of IRE and the reasons for tumor relapse. We hypothesized that, we could identify a molecular rationale for the tumor recurrence and potential co-therapy targets for IRE treatment. We have utilized Pan02 cells, and a subcutaneous flank model of pancreatic cancer. Here, we show that IRE can significantly delay cancer progression by shifting the tumor microenvironment to a pro-inflammatory state. In doing so, IRE treatment recruits cytotoxic CD8+ T-cells to the tumor sites, reduces contralateral tumor burden, and increases interferon-gamma (IFNγ) levels in the serum. Within two weeks after treatment, immune cells in the tumor site reverts to the pre-treatment condition, tumor relapses, and tumor cells express programmed-cell death-ligand 1 (PD-L1). Our in vitro findings of IFNγ dependent PD-L1 expression and ineffective in vivo blocking of IFNγ hints feedback loop pathway involving IFNγ and PD-L1. Since other findings have shown blocking PD-L1 is not always very effective, our findings indicate another compensatory bypass immune checkpoint mechanism. The effects of IRE can therefore be extended by additional combination therapy methods, including PD-1/PD-L1 antibody immunotherapies, and small molecule inhibitors. This work was supported, in part, by the Virginia Maryland College of Veterinary Medicine; The Virginia Tech Institute for Critical Technology and Applied Sciences Center for Engineered Health; and The National Institutes of Health (R03AI151494 (ICA); R21EB028429 (ICA). The contents solely the responsibility of the authors and does not necessarily represent the official views of the NIH or any other funding agency.