Irreversible electroporation ablation overcomes tumor-associated immunosuppression to improve the efficacy of DC vaccination in a mice model of pancreatic cancer

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is associated with highly immunosuppressive tumor microenvironment (TME) that can limit the efficacy of dendritic cell (DC) vaccine immunotherapy. Irreversible electroporation (IRE) is a local ablation approach. Herein, we test the hypothesis that IRE ablation can overcome TME immunosuppression to improve the efficacy of DC vaccination using Kras LSL-G12D -p53 LSL-R172H -Pdx-1-Cre (KPC) orthotopic mouse model of PDAC. The median survival for mice treated with the combined IRE and DC vaccination was 77 days compared with sham control (35 days), DC vaccination (49 days), and IRE (44 days) groups (P = .006). Thirty-six percent of the mice treated with combination IRE and DC vaccination were still survival at the end of the study period (90 days) without visible tumor. The changes of tumor apparent diffusion coefficient (ΔADC) were higher in mice treated with combination IRE and DC vaccination than that of other groups (all P < .001); tumor ΔADC value positively correlated with tumor fibrosis fraction (R = 0.707, P < .001). IRE induced immunogenic cell death and alleviation of immunosuppressive components in PDAC TME when combined with DC vaccination, including increased tumor infiltration of CD8 + T cells and Granzyme B + cells (P = .001, and P = .007, respectively). Our data show that IRE ablation can overcome TME immunosuppression to improve the efficacy of DC vaccination in PDAC. Combination IRE ablation and DC vaccination may enhance therapeutic efficacy for PDAC.

Pancreatic Cancer and Immunotherapy: A Clinical Overview

“…IRE has demonstrated the ability to temporarily lift immune-suppressive barriers and to elicit an anti-tumor immune response in PDAC patients [224,225]. Consequently, the feasibility of combined IRE with immunotherapy, coined as 'electroimmunotherapy' [226], was examined in pre-clinical immunocompetent PDAC murine models, resulting in significant tumor regression, increased CD8 + T cell infiltration and improved survival [137,[227][228][229]. In a clinical setting, percutaneous IRE has been combined with allogeneic NK cell therapy [219].…”

Irreversible Electroporation Plus Anti-PD-1 Antibody versus Irreversible Electroporation Alone for Patients with Locally Advanced Pancreatic Cancer

“… 9 Additionally, IRE could also enhance the process of antigen presentation by promoting M1 macrophage polarization and maturation of dendritic cells. 10 , 19 Based on these findings, a promising approach to improve the responsiveness of ICIs is to utilize the immunogenic properties of IRE to increase the cytotoxic T cells (CTL) to the “cold” TME, switching its immune status to “hot”. The combination of IRE and PD-1 immune checkpoint blockade could significantly promote survival in Kras-induced pancreatic cancer (KPC) mode by selectively promoting the infiltration of CD8 + T cells.…”

Immunomodulatory Effect of Irreversible Electroporation Alone and Its Cooperating With Immunotherapy in Pancreatic Cancer

“…Yang et al reported that IRE would overcome tumor microenvironment immunosuppression to improve the efficacy of DC cell vaccine in a mice model of PC. Their combination may cause immunogenic cell death and relieve immunosuppressive components in PC microenvironment, including increased tumor infiltration of CD8+ T cells and B+ cells(63), which well indicated that this combination exerted a synergistic effect to enhance the therapeutic efficacy of patients.Oncolytic virotherapy meant that oncolytic viruses selectively disrupted tumor tissues by directly lysing cells, causing systemic antitumor immunity, or regulating tumor vasculature(64). M1 virus could kill residual cancer cells following IRE.…”