Department of Pancreatobiliary Surgery, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, P. R. China.
State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, Guangdong, P.R. China.
Oncoimmunology. 2021 Mar 11;10(1):1897295. doi: 10.1080/2162402X.2021.1897295.
Irreversible electroporation (IRE) is an effective method for treating pancreatic ductal adenocarcinoma (PDAC). It remains unclear whether IRE can induce a specific immune response by stimulating macrophages. Here, the associated markers of macrophages were analyzed after exposure to tumor culture supernatant (TSN) of tumor cells treated with electroporation. Subcutaneous and orthotopic PDAC models were also used to evaluate the effect of macrophage polarization induced by IRE. Aside from its direct killing effect, IRE could induce the immunogenic cell death of tumor cells by increasing the synthesis and secretion of damage associated molecular patterns. Moreover, IRE could increase the release of HMGB1, which activates the MAPK-p38 pathway and leads to the increased expression of M1 markers in macrophages, through binding to the receptor of the advanced glycation end-product (RAGE) receptor. M1 polarization was inhibited by the inhibitors of HMGB1 release, the RAGE receptor, and the MAPK-p38 signaling pathway, but it was activated by rHMGB1 or the stimulator of MAPK-p38. In addition, the promotion of M1 macrophage polarization was enhanced by the positive-feedback release or expression of HMGB1 and RAGE through the MAPK-ERK pathway in macrophages. The promotion of M1 macrophage polarization induced by IRE provided a specific rationale for the combination of IRE and immune therapy in treating PDAC.
不可逆电穿孔 (IRE) 是治疗胰腺导管腺癌 (PDAC) 的有效方法。目前尚不清楚 IRE 是否可以通过刺激巨噬细胞来诱导特异性免疫反应。在此，分析了用电穿孔处理后的肿瘤细胞的肿瘤培养上清液 (TSN) 作用下巨噬细胞相关标志物的变化。还使用皮下和原位 PDAC 模型来评估 IRE 诱导的巨噬细胞极化的效果。IRE 除了直接杀伤作用外，还可以通过增加损伤相关分子模式的合成和分泌来诱导肿瘤细胞的免疫原性细胞死亡。此外，IRE 通过与晚期糖基化终产物 (RAGE) 受体结合，增加 HMGB1 的释放，激活 MAPK-p38 通路，从而导致巨噬细胞中 M1 标志物的表达增加。HMGB1 释放的抑制剂、RAGE 受体和 MAPK-p38 信号通路抑制剂均可抑制 M1 极化，但 rHMGB1 或 MAPK-p38 的刺激物可激活 M1 极化。此外，通过 MAPK-ERK 通路在巨噬细胞中促进 HMGB1 和 RAGE 的正反馈释放或表达，可增强 IRE 诱导的 M1 巨噬细胞极化。IRE 诱导的 M1 巨噬细胞极化的促进为 IRE 与免疫疗法联合治疗 PDAC 提供了具体的理论依据。
