The generation of PD-L1 and PD-L2 in cancer cells: From nuclear chromatin reorganization to extracellular presentation.
The generation of PD-L1 and PD-L2 in cancer cells: From nuclear chromatin reorganization to extracellular presentation.
复制标题
癌细胞中 PD-L1 和 PD-L2 的生成：从核染色质重组到细胞外呈递
DOI：
10.1016/j.apsb.2021.09.010
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发表时间：
2022-03
影响因子：
14.5
通讯作者：
Fan, Yihui
中科院分区：
文献类型：
--
作者：
Fan, Zhiwei;Wu, Changyue;Chen, Miaomiao;Jiang, Yongying;Wu, Yuanyuan;Mao, Renfang;Fan, Yihui
关键词：
靶向PD-1/PD-L1的免疫检查点阻断（ICB）在治疗癌症方面显示出显着的前景。然而，低有效率和经常观察到的严重副作用限制了其广泛的益处。部分原因是由于对PD-L1的生物学调控了解较少。本文系统、全面地综述了PD-L1从核染色质重组到细胞外递呈的调控过程。在PD-L1和PD-L2高表达的癌细胞中，在CD274和CD273周围发现了一个新的TAD（拓扑相关结构域）（chr9: 5,400,000-5,600,000），其中包括一个报道的驱动PD-L1和PD-L2同步转录的超级增强子。重新塑造的TAD允许转录因子如STAT3和IRF1招募到PD-L1位点，以指导PD-L1的表达。转录后，PD-L1通过长3'UTR受到mirna和rna结合蛋白的严格调控。在翻译水平上，PD-L1蛋白及其膜递呈受到糖基化和泛素化等翻译后修饰的严格调控。此外，PD-L1可以通过外泌体分泌，系统地抑制免疫反应。因此，全面剖析PD-L1/PD-L2的调控机制，深入检测PD-L1/PD-L2及其调控网络，将为ICB及基于ICB的联合治疗带来更多见解。患者体内PD-L1/L2的水平和特征在很大程度上决定了免疫检查点阻断的治疗效果。PD-L1/L2被精确调控，其特性是通过复杂的网络建立的。
The immune checkpoint blockade (ICB) targeting on PD-1/PD-L1 has shown remarkable promise in treating cancers. However, the low response rate and frequently observed severe side effects limit its broad benefits. It is partially due to less understanding of the biological regulation of PD-L1. Here, we systematically and comprehensively summarized the regulation of PD-L1 from nuclear chromatin reorganization to extracellular presentation. In PD-L1 and PD-L2 highly expressed cancer cells, a new TAD (topologically associating domain) (chr9: 5,400,000–5,600,000) around CD274 and CD273 was discovered, which includes a reported super-enhancer to drive synchronous transcription of PD-L1 and PD-L2. The re-shaped TAD allows transcription factors such as STAT3 and IRF1 recruit to PD-L1 locus in order to guide the expression of PD-L1. After transcription, the PD-L1 is tightly regulated by miRNAs and RNA-binding proteins via the long 3′UTR. At translational level, PD-L1 protein and its membrane presentation are tightly regulated by post-translational modification such as glycosylation and ubiquitination. In addition, PD-L1 can be secreted via exosome to systematically inhibit immune response. Therefore, fully dissecting the regulation of PD-L1/PD-L2 and thoroughly detecting PD-L1/PD-L2 as well as their regulatory networks will bring more insights in ICB and ICB-based combinational therapy. The level and characteristics of PD-L1/L2 in patients largely determine therapeutic efficacy to immune checkpoint blockade. PD-L1/L2 are precisely regulated and their characteristics are established by a complicated network.
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影响因子：
14.9
作者：
An O;Dall'Olio GM;Mourikis TP;Ciccarelli FD
通讯作者：
Ciccarelli FD
影响因子：
--
作者：
Carbotti G;Barisione G;Airoldi I;Mezzanzanica D;Bagnoli M;Ferrero S;Petretto A;Fabbi M;Ferrini S
通讯作者：
Ferrini S
DOI：
10.1126/science.aac9935
发表时间：
2016-04-08
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Casey SC;Tong L;Li Y;Do R;Walz S;Fitzgerald KN;Gouw AM;Baylot V;Gütgemann I;Eilers M;Felsher DW
通讯作者：
Felsher DW
影响因子：
16
作者：
Cordonnier, Marine;Nardin, Charlee;Gobbo, Jessica
通讯作者：
Gobbo, Jessica
影响因子：
64.8
作者：
Burr ML;Sparbier CE;Chan YC;Williamson JC;Woods K;Beavis PA;Lam EYN;Henderson MA;Bell CC;Stolzenburg S;Gilan O;Bloor S;Noori T;Morgens DW;Bassik MC;Neeson PJ;Behren A;Darcy PK;Dawson SJ;Voskoboinik I;Trapani JA;Cebon J;Lehner PJ;Dawson MA
通讯作者：
Dawson MA