Division of Surgical Oncology, Hiram C. Polk Jr. M.D. Department of Surgery, University of Louisville School of Medicine, Louisville, KY, USA.
Department of Pharmacology & Toxicology, University of Louisville School of Medicine, Louisville, KY, USA.
Ann Surg Oncol. 2019 Mar;26(3):800-806. doi: 10.1245/s10434-018-07144-3. Epub 2019 Jan 4.
Irreversible electroporation (IRE) has been demonstrated as an effective local method for locally advanced (stage 3) pancreatic adenocarcinoma. Immune regulatory T cells (Tregs) induce immunosuppression of tumors by inhibiting patients' anti-tumor adaptive immune response. This study aimed to evaluate the immunomodulation effect of IRE to identify an ideal time point for potential adjuvant immunotherapy.
This study prospectively evaluated an institutional review board-approved study of patients undergoing either in situ IRE or pancreatectomy. Patient blood samples were collected at different time points (before surgery [preOP] and on postoperative day [POD] 1, POD3, and POD5). Peripheral blood mononuclear cells (PBMCs) were isolated and evaluated for three different CD4 + Treg subsets (CD25 + CD4 +, CD4 + CD25 + FoxP3 +, CD4 + CD25 + FoxP3 -) by flow cytometry and analyzed for median fold change (MFC) between each two consecutive time points (MFC = log2(T2/T1)).
The study analyzed 15 patients with in situ IRE (n = 11) or pancreatectomy (PAN) (n = 4). In both groups, CD25 + CD4 + Tregs decreased on POD1 followed by a steady increase in pancreatectomy, whereas the trend in the IRE group reversed between D3 and D5 (MFC: IRE [- 0.01], PAN [+ 0.39]). For each period, CD4 + CD25 + FoxP3 + Tregs showed the most dramatic inverse effect, with D3 to D5 showing the most change (MFC: IRE [- 0.18], PAN [+ 0.39]). Also, CD4 + CD25 + FoxP3 - Tregs showed an inverse effect between D3 and D5 (MFC: IRE [- 0.25], PAN [+ 0.49]). Altogether, the Treg trend was inversely affected by the in situ IRE procedure, with the greatest cumulative significant change for all three Treg subsets between D3 and D5 (MFC ± SEM: IRE [- 0.24 ± 0.05], PAN [+ 0.37 ± 0.02]; p = 0.016).
The study data suggest that in situ IRE procedure-mediated Treg attenuation between POD3 and POD5 can provide a clinical window of opportunity for potentiating clinical efficacy in combination with immunotherapy.
不可逆电穿孔（IRE）已被证明是局部治疗局部晚期（3 期）胰腺腺癌的有效方法。免疫调节性 T 细胞（Tregs）通过抑制患者的抗肿瘤适应性免疫反应来诱导肿瘤的免疫抑制。本研究旨在评估 IRE 的免疫调节作用，以确定潜在辅助免疫治疗的理想时间点。
本研究前瞻性评估了一项机构审查委员会批准的接受原位 IRE 或胰腺切除术患者的研究。患者在不同时间点（手术前[术前]和术后第 1 天[POD1]、第 3 天[POD3]和第 5 天[POD5]）采集外周血单核细胞（PBMC）。通过流式细胞术分离外周血单核细胞（PBMC），并评估三种不同的 CD4+Treg 亚群（CD25+CD4+、CD4+CD25+FoxP3+、CD4+CD25+FoxP3-），并分析每两个连续时间点之间的中位数倍数变化（MFC）（MFC=log2（T2/T1））。
该研究分析了 15 例接受原位 IRE（n=11）或胰腺切除术（PAN）（n=4）的患者。在两组中，CD25+CD4+Tregs 在 POD1 时减少，随后在胰腺切除术组中稳定增加，而 IRE 组在 D3 和 D5 之间的趋势相反（MFC：IRE[-0.01]，PAN[+0.39]）。对于每个时期，CD4+CD25+FoxP3+Tregs 显示出最显著的相反效应，D3 至 D5 显示出最大的变化（MFC：IRE[-0.18]，PAN[+0.39]）。此外，CD4+CD25+FoxP3-Tregs 在 D3 和 D5 之间显示出相反的效应（MFC：IRE[-0.25]，PAN[+0.49]）。总之，原位 IRE 程序对 Treg 产生了相反的影响，在 D3 和 D5 之间，所有三种 Treg 亚群的累积变化最大（MFC±SEM：IRE[-0.24±0.05]，PAN[+0.37±0.02]；p=0.016）。
研究数据表明，在原位 IRE 程序介导的 Treg 衰减之间，POD3 和 POD5 可以为免疫治疗联合治疗提供增强临床疗效的临床机会窗口。
