Integrative Omics Analyses Reveal Molecular Changes of Irreversible Electroporation on Pancreatic cancer in Mice

Abstract

Abstract Purpose Irreversible electroporation (IRE) is a local ablative technique with encouraging results in treatment of pancreatic cancer. However, the high recurrence rates make adjuvant therapy necessary. To develop effective adjuvant therapies with IRE, we aimed to analyze the molecular changes of pancreatic cancer after IRE.. Methods KPC cell line was used to set subcutaneous or orthotopic pancreatic cancer mouse models. Both models were randomized to either sham surgery and IRE, and named control group or IRE group, respectively. The subcutaneous tumor models were used to evaluate IRE efficacy by recording the tumor volume and survival time. Orthotopic tumor models were employed to analyze the molecular changes of tumor tissues using transcriptomics, proteomics, and single-cell RNA sequencing (scRNA-seq) a day after IRE. Results IRE transiently inhibited tumor growth and prolonged the survival time of subcutaneous tumor models. Transcriptomics and proteomics analyses showed that T helper 1 (Th1) and T helper 2 (Th2) cell differentiation as well as T helper 17 (Th17) cell differentiation pathways were most significantly downregulated in the IRE group compared with the control group, indicating that IRE significantly affected CD4+ T cells. Furthermore, scRNA-seq revealed that the proportion of CD4+ effector T cell of CD4+ T cells decreased significantly, whereas the proportions of CD4+ naive T cells and regulatory T cell (Tregs) increased significantly in the IRE group. Gene set enrichment analysis revealed that tumor necrosis factor (TNF) and interleukin (IL)-17 signaling pathways of CD4+ effector T cells, and the IL-17 signaling pathway of CD4+ naive cells were significantly downregulated after IRE. Conclusions IRE can effectively treat pancreatic cancer in mice and significantly altered the distribution and functions of CD4+ T cells in pancreatic cancer.