Qiu Nasha, Liu Yun, Liu Qi, Chen Yanzuo, Shen Limei, Hu Mengying, Zhou Xuefei, Shen Youqing, Gao Jianqing, Huang Leaf
Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, United States; Zhejiang Key Laboratory of Key Materials for Precision Medicine and Center for Bionanoengineering, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou, 310027, China; Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, United States.
Biomaterials. 2021 Feb;269:120604. doi: 10.1016/j.biomaterials.2020.120604. Epub 2020 Dec 17.
Programmed cell death-ligand 1 (PD-L1)-based immune checkpoint blockade therapy using the anti-PD-L1 antibody is effective for a subset of patients with advanced metastatic melanoma but about half of the patients do not respond to the therapy because of the tumor immunosuppressive microenvironment. Immunogenic cell death (ICD) induced by cytotoxins such as doxorubicin (DOX) allows damaged dying tumor cells to release immunostimulatory danger signals to activate dendritic cells (DCs) and T-cells; however, DOX also makes tumor cells upregulate PD-L1 expression and thus deactivate T-cells via the PD-1/PD-L1 pathway. Herein, we show that celastrol (CEL) induced not only strong ICD but also downregulation of PD-L1 expression of tumor cells. Thus, CEL was able to simultaneously activate DCs and T-cells and interrupt the PD-1/PD-L1 pathway between T-cells and tumor cells. In a bilateral tumor model, intratumorally (i.t.) injected celastrol nanoemulsion retaining a high tumor CEL concentration activated the immune system efficiently, which inhibited both the treated tumor and the distant untreated tumor in the mice (i.e., abscopal effect). Thus, this work demonstrates a new and much cost-effective immunotherapy strategy - chemotherapy-induced immunotherapy against melanoma without the need for expensive immune-checkpoint inhibitors.
使用抗程序性死亡配体1（PD-L1）抗体的基于PD-L1的免疫检查点阻断疗法对一部分晚期转移性黑色素瘤患者有效，但约一半的患者由于肿瘤免疫抑制微环境而对该疗法无反应。阿霉素（DOX）等细胞毒素诱导的免疫原性细胞死亡（ICD）可使受损的垂死肿瘤细胞释放免疫刺激危险信号，从而激活树突状细胞（DC）和T细胞；然而，DOX也会使肿瘤细胞上调PD-L1表达，进而通过PD-1/PD-L1途径使T细胞失活。在此，我们表明，雷公藤红素（CEL）不仅能诱导强烈的ICD，还能下调肿瘤细胞的PD-L1表达。因此，CEL能够同时激活DC和T细胞，并中断T细胞与肿瘤细胞之间的PD-1/PD-L1途径。在双侧肿瘤模型中，瘤内（i.t.）注射保留高肿瘤CEL浓度的雷公藤红素纳米乳剂可有效激活免疫系统，抑制小鼠体内已治疗的肿瘤和远处未治疗的肿瘤（即远隔效应）。因此，这项研究展示了一种新的且成本效益更高的免疫治疗策略——无需昂贵免疫检查点抑制剂的针对黑色素瘤的化疗诱导免疫疗法。
