PDF(Pubmed)
Abstract：
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.
摘要：
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著的希望。然而,低反应率和经常观察到的严重副作用限制了其广泛的益处.部分原因是对PD-L1的生物学调控了解较少。这里,我们系统全面地总结了PD-L1从核染色质重组到细胞外呈递的调控。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（拓扑关联域）（chr9：5,400,000-5,600,000），其中包括报道的超级增强子以驱动PD-L1和PD-L2的同步转录。重新成形的TAD允许转录因子如STAT3和IRF1募集到PD-L1基因座以指导PD-L1的表达。转录后,PD-L1通过长3UTR受到miRNA和RNA结合蛋白的严格调控。在翻译层面,PD-L1蛋白及其膜呈递受到翻译后修饰如糖基化和泛素化的严格调节。此外,PD-L1可以通过外泌体分泌以系统地抑制免疫应答。因此,全面剖析PD-L1/PD-L2的调节，彻底检测PD-L1/PD-L2及其调节网络将为ICB和基于ICB的组合治疗带来更多见解。
