在肝细胞癌小鼠模型中，减毒沙门氏菌联合奥沙利铂递送 SiRNA-PD-L1。
Delivery of SiRNA-PD-L1 by attenuated Salmonella in combination with oxaliplatin in a hepatocellular carcinoma mouse model.
发表日期：2024 Aug 14
作者：
Pengfei Chen, Jinwei Chen, Baozhu Li, Yige Zhang, Kun Li, Chuyang Shao, Panpan Guo, Tongguo Yang, Hongjun Liu, Xiaolong Jia, Xuhua Duan, Tiesuo Zhao, Huijie Jia, Jianzhuang Ren
来源：
INTERNATIONAL IMMUNOPHARMACOLOGY
摘要：
奥沙利铂目前用于肝细胞癌患者的化疗，但随着时间的推移，其对肿瘤的耐受性不断增强，限制了其临床应用。研究表明，PD-L1的高表达会促进M2巨噬细胞的极化。 M2巨噬细胞（包括HCC中的M2巨噬细胞）浸润增加与各种实体瘤的不良预后呈正相关。我们发现奥沙利铂促进肝癌细胞中PD-L1的表达，这可能部分归因于肿瘤对奥沙利铂的耐受。因此，在本研究中，我们通过Western blotting、免疫组化、免疫荧光和流式细胞术探讨了携带siRNA-PD-L1的减毒沙门氏菌联合奥沙利铂的抗肿瘤作用。结果显示，携带siRNA-PD-L1的减毒沙门氏菌联合奥沙利铂更显着地抑制荷瘤小鼠的肿瘤生长，抑制肿瘤组织中PD-L1的表达，增加肿瘤细胞的凋亡和肿瘤相关蛋白的表达。相关蛋白cleaved-caspase3，增加肿瘤组织中M1巨噬细胞和T淋巴细胞的浸润。此外，联合疗法增加了小鼠脾脏中T细胞的活化以及T淋巴细胞和NK细胞的数量，并改善了小鼠的整体抗肿瘤免疫反应。我们的研究结果证实，携带siRNA-PD-L1的减毒沙门氏菌联合奥沙利铂具有显着的抗肿瘤作用，且未增加毒副作用的发生率，为解决肝细胞癌治疗中的奥沙利铂耐受问题提供了理论参考。版权所有 © 2024 Elsevier B.V.保留所有权利。
Oxaliplatin is currently used for chemotherapy in patients with hepatocellular carcinoma, but its increasing tolerance to tumours over time limits its clinical application. Studies have shown that high PD-L1 expression promotes the polarization of M2 macrophages. The increased infiltration of M2 macrophages, including those in HCC, is positively correlated with poor prognosis in various solid tumours. We found that oxaliplatin promoted the expression of PD-L1 in liver cancer cells, which might be attributed partly to the tolerance of tumours to oxaliplatin. Therefore, in this study, we explored the antitumour effect of attenuated Salmonella carrying siRNA-PD-L1 combined with oxaliplatin via Western blotting, immunohistochemistry, immunofluorescence, and flow cytometry. The results revealed that attenuated Salmonella carrying siRNA-PD-L1 combined with oxaliplatin more significantly inhibited tumour growth in tumour-bearing mice, suppressed the expression of PD-L1 in tumour tissue, increased the apoptosis of tumour cells and the expression of the tumour-related protein cleaved-caspase3, and increased the infiltration of M1 macrophages and T lymphocytes in tumour tissues. Moreover, the combination therapy increased the activation of T cells and the number of T lymphocytes and NK cells in the spleens of the mice and improved the overall antitumour immune response in the mice. Our results confirmed that attenuated Salmonella harbouring siRNA-PD-L1 combined with oxaliplatin had a significant antitumour effect and did not increase the incidence of toxic side effects, providing a theoretical reference for addressing oxaliplatin tolerance in the treatment of hepatocellular carcinoma.Copyright © 2024 Elsevier B.V. All rights reserved.