Celastrol nanoemulsion induces immunogenicity and downregulates PD-L1 to boost abscopal effect in melanoma therapy

被引:71
作者
Qiu, Nasha [1 ,2 ,3 ,4 ]
Liu, Yun [1 ]
Liu, Qi [1 ]
Chen, Yanzuo [1 ]
Shen, Limei [1 ]
Hu, Mengying [1 ]
Zhou, Xuefei [1 ]
Shen, Youqing [2 ,3 ]
Gao, Jianqing [4 ]
Huang, Leaf [1 ]
机构
[1] Univ North Carolina Chapel Hill, Div Pharmacoengn & Mol Pharmaceut, Eshelman Sch Pharm, Chapel Hill, NC 27599 USA
[2] Zhejiang Univ, Coll Chem & Biol Engn, Zhejiang Key Lab Key Mat Precis Med, Hangzhou 310027, Peoples R China
[3] Zhejiang Univ, Coll Chem & Biol Engn, Ctr Bionanoengn, Hangzhou 310027, Peoples R China
[4] Zhejiang Univ, Coll Pharmaceut Sci, Inst Pharmaceut, Hangzhou 310058, Peoples R China
基金
美国国家卫生研究院; 中国国家自然科学基金;
关键词
Celastrol nanoemulsion; Cancer immunotherapy; Immunogenic cell death; PD-L1; downregulation; Abscopal effect;
D O I
10.1016/j.biomaterials.2020.120604
中图分类号
R318 [生物医学工程];
学科分类号
0831 ;
摘要
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 costeffective immunotherapy strategy - chemotherapy-induced immunotherapy against melanoma without the need for expensive immune-checkpoint inhibitors.
引用
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页数:14
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