Zhiwei Fan, Changyue Wu, Miaomiao Chen, Yongying Jiang, Yuanyuan Wu, Renfang Mao, Yihui Fan. The generation of PD-L1 and PD-L2 in cancer cells: From nuclear chromatin reorganization to extracellular presentation[J]. Acta Pharmaceutica Sinica B, 2022, 12(3): 1041-1053

The generation of PD-L1 and PD-L2 in cancer cells: From nuclear chromatin reorganization to extracellular presentation
Zhiwei Fana,b, Changyue Wub,c, Miaomiao Chenb, Yongying Jiangd, Yuanyuan Wub, Renfang Maod, Yihui Fana,b
a. Department of Pathogenic Biology, School of Medicine, Nantong University, Nantong 226001, China;
b. Laboratory of Medical Science, School of Medicine, Nantong University, Nantong 226001, China;
c. Department of Dermatology, Affiliated Hospital of Nantong University, Nantong University, Nantong 226001, China;
d. Department of Pathophysiology, School of Medicine, Nantong University, Nantong 226001, China
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.
Key words:    Immune checkpoint blockade    PD-L1    PD-L2    Topologically associating domain    Transcription    Post-transcriptional regulation    Post-translational regulation    Exosome   
Received: 2021-06-15     Revised: 2021-07-27
DOI: 10.1016/j.apsb.2021.09.010
Funds: This work was supported by the National Natural Science Foundation of China (31970616; 31770935; 81873531; and 82070505), the Distinguished Professorship Program of Jiangsu Province to Yihui Fan, the Distinguished Professorship Program of Jiangsu Province to Renfang Mao, The National Undergraduate Training Programs for Innovation (202010304109Y, China). We would like to acknowledge the 3D genome browser ( for free use. We apologize to colleagues whose work was not cited in this review owing to space constraints.
Corresponding author: Yuanyuan Wu,;Renfang Mao,;Yihui Fan,;;
Author description:
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Zhiwei Fan
Changyue Wu
Miaomiao Chen
Yongying Jiang
Yuanyuan Wu
Renfang Mao
Yihui Fan

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