Immunomodulatory Effect after Irreversible Electroporation in Patients with Locally Advanced Pancreatic Cancer

He, Chaobin; Wang, Jun; Sun, Shuxin; Zhang, Yu; Li, Shengping

In this study, an immunomodulatory effect was demonstrated by altering lymphocytes, cytokines, and humoral immune parameters in patients with LAPC after IRE. It was the first evidence for IRE-based immune modulation in LAPC patients. It was shown that there was a transitory decrease followed by a steady increase for CD4 + T cell, CD8 + T cell, NK cell, IL-2, C3, C4, and IgG while a reverse trend was observed 8 Journal of Oncology Table 1 Journal of Oncology 9 Table 3 10 Journal of Oncology Abbreviations as in Table 3 for Treg cell, IL-6, and IL10 after IRE. Other circulating cytokines, including TNF and IFN, were also evaluated. In terms of IFN, IFN-plays the most important role in its immunostimulatory and immunomodulatory effects, compared with the ability to inhibit viral replication directly, which is the main function of IFN- [23, 24] or IFN-ß [25] . Therefore, IFN-and TNF were analyzed while they both failed to show obvious alteration. In addition, the alteration of CD8 + T cell between D3 and D7 was identified as prognostic factor for OS and PFS and first showed both a convenient and effective prognostic value in patients with LAPC after IRE. When compared with the traditional inflammationbased scores, the alteration of CD8 + T cell exhibited a better predictive value for both OS and PFS. For LAPC patients after ablation therapy, several studies have revealed the changes of individual counts of T cell and subset ratios [26] [27] [28] . Alessandro G et al. compared the concentration of CD4 + and CD8 + T cell before and after radiofrequency ablation (RFA) and revealed an increase of above-mentioned T cells from the third day after treatment [26] . In the study conducted by Ketevan M et al., a more significant decrease in the expression of CD4 + CD39 + T cell was observed after RFA, compared with operation [27] . In animal study, IRE therapy, which induced an increase tumor infiltration of CD3 + cells, was reported to be more effective in immunocompetent tumor than in immunocompromised tumors [28] . Furthermore, Martin et al. reported that IRE induced an obvious decrease in the absolute number of Treg cell in patients with LAPC [29] . Similar to Martin's study, our study showed a transitory increase followed by a remarkable decrease for Treg cell, along with a steady increase of effective T cells and humoral immune parameters after IRE. As an inflammation-inducing treatment, IRE not only directly destroys tumor cells, but also results in a release of tumor-associated neoantigens, which may stimulate the cellular and humoral immune of the body. Then, the numbers of immunocytes and production of humoral immune parameters will increase due to the potentiation of cellular and humoral immune. Moreover, it was shown that heatshock proteins released from the destroyed tumor cells had an adjuvant effect and acted as an alarm for antitumor T cell-mediated immunity [30] . Therefore, IRE may be a mean of significant effort to overcome the immunosuppressive "cold" tumor microenvironment in LAPC and a potential treatment window of opportunity for immune-check-point therapy was suggested by increasing the effector T cells and decreasing immunosuppressive Treg cells. In addition, for these patients, prior biliary drainage procedure or a hepaticojejunostomy during open procedure was performed. Also, no serious complications, such as abdominal infection and pancreatic fistula, were observed in all patients after IRE therapy. Therefore, the influence