Celastrol nanoemulsion induces immunogenicity and downregulates PD-L1 to boost abscopal effect in melanoma therapy.
Celastrol nanoemulsion induces immunogenicity and downregulates PD-L1 to boost abscopal effect in melanoma therapy.
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雷公藤红素纳米乳诱导免疫原性并下调 PD-L1 以增强黑色素瘤治疗中的远隔效应
DOI：
10.1016/j.biomaterials.2020.120604
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发表时间：
2021-03
期刊：
影响因子：
14
通讯作者：
Huang L
中科院分区：
文献类型：
--
作者：
Qiu N;Liu Y;Liu Q;Chen Y;Shen L;Hu M;Zhou X;Shen Y;Gao J;Huang L
使用抗PD-L1抗体的基于程序性细胞死亡配体1（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，但由于肿瘤免疫抑制微环境，约一半的患者对该疗法无反应。多柔比星（DOX）等细胞毒素诱导的免疫原性细胞死亡（ICD）允许受损的垂死肿瘤细胞释放免疫刺激危险信号来激活树突状细胞（DC）和T细胞;然而，DOX也使肿瘤细胞上调PD-L1表达，从而通过PD-1/PD-L1途径使T细胞失活。在此，我们发现雷公藤红素（CEL）不仅诱导强ICD，而且下调肿瘤细胞的PD-L1表达。因此，CEL能够同时激活DC和T细胞，并中断T细胞和肿瘤细胞之间的PD-1/PD-L1通路。在双侧肿瘤模型中，瘤内（i.t.）注射保留高肿瘤CEL浓度的南蛇藤素纳米乳液有效激活免疫系统，从而抑制小鼠中治疗的肿瘤和远处未治疗的肿瘤（即，远位效应）。因此，这项工作证明了一种新的和更具成本效益的免疫治疗策略-化疗诱导的免疫治疗黑色素瘤，而不需要昂贵的免疫检查点抑制剂。
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 active 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.
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影响因子：
7.4
作者：
Madonna G;Ullman CD;Gentilcore G;Palmieri G;Ascierto PA
通讯作者：
Ascierto PA
影响因子：
12.4
作者：
Hou L;Liu Q;Shen L;Liu Y;Zhang X;Chen F;Huang L
通讯作者：
Huang L
DOI：
10.4049/jimmunol.1490019
发表时间：
2014-06-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Rosenberg SA
通讯作者：
Rosenberg SA
影响因子：
51.1
作者：
Ribas, Antoni;Puzanov, Igor;Dummer, Reinhard;Schadendorf, Dirk;Hamid, Omid;Robert, Caroline;Hodi, F. Stephen;Schachter, Jacob;Pavlick, Anna C.;Lewis, Karl D.;Cranmer, Lee D.;Blank, Christian U.;O'Day, Steven J.;Ascierto, Paolo A.;Salama, April K. S.;Margolin, Kim A.;Loquai, Carmen;Eigentler, Thomas K.;Gangadhar, Tara C.;Carlino, Matteo S.;Agarwala, Sanjiv S.;Moschos, Stergios J.;Sosman, Jeffrey A.;Goldinger, Simone M.;Shapira-Frommer, Ronnie;Gonzalez, Rene;Kirkwood, John M.;Wolchok, Jedd D.;Eggermont, Alexander;Li, Xiaoyun Nicole;Zhou, Wei;Zernhelt, Adriane M.;Lis, Joy;Ebbinghaus, Scot;Kang, S. Peter;Daud, Adil
通讯作者：
Daud, Adil
雷公藤红素诱导的 Nur77 与 TRAF2 相互作用通过促进线粒体泛素化和自噬减轻炎症
影响因子：
16
作者：
Hu M;Luo Q;Alitongbieke G;Chong S;Xu C;Xie L;Chen X;Zhang D;Zhou Y;Wang Z;Ye X;Cai L;Zhang F;Chen H;Jiang F;Fang H;Yang S;Liu J;Diaz-Meco MT;Su Y;Zhou H;Moscat J;Lin X;Zhang XK
通讯作者：
Zhang XK