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Blocking PD-L1 for anti-liver cancer immunity: USP22 represents a critical cotarget

Cellular & Molecular Immunology volume 17, pages 677–679 (2020)Cite this article

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To date, the PD-1/PD-L1 blockade strategy has been tested in a variety of cancer types. However, only bladder cancer, melanoma, mismatch repair-deficient colorectal cancer, and certain hematopoietic malignancies have been highly responsive in terms of clinical outcomes.1,2 It is presumed that the expression level of the PD-L1 protein largely determines the therapeutic efficacy of PD-1/PD-L1-targeted cancer immunotherapy.3,4 Previous studies have shown that several transcriptional factors are involved in the upregulation of PD-L1 by directly binding to its promoter region.5 For instance, individual activation of STAT1, NF-κB, HIF-1α, c-Myc, or MAPK increased PD-L1 transcription and immune evasion of tumor cells. On the other hand, oncogenic RAS signaling reportedly stabilizes PD-L1 mRNA to promote tumor immunoresistance.6

In addition to transcriptional and translational regulation, the protein stability of PD-L1 is controlled at multiple points at the posttranslational level, which is hypothesized to be one of the leading causes of PD-1/PD-L1-targeted immunotherapy inefficiency and resistance to it. Thus far, all phosphorylation, glycosylation, palmitoylation, ubiquitination, methylation, and acetylation modifications have been found to be involved in the posttranslational modification (PTM) of PD-L1.5,7 The phosphorylation of PD-L1 is frequently observed in multiple cancers. GSK3β can directly bind to the C-terminal domain of PD-L1 and phosphorylate the T180 and S184 residues on PD-L1, which are subsequently recognized by β-TRCP to negatively affect PD-L1 stability and thus enhance PD-1 blockade therapy.8 On the other hand, PD-L1 can be modified by N-linked glycosylation, which stabilizes PD-L1 primarily by preventing GSK3β/β-TRCP-mediated PD-L1 degradation. In addition, Cha et al. found that metformin-activated AMPK directly phosphorylates PD-L1 at the S195 residue to induce abnormal glycosylation, which results in PD-L1 degradation through the ERAD pathway.9

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Fig. 1: USP22 dominates PD-L1 deubiquitination in liver cancer to suppress antitumor immunity, while CSN5 contributes to PD-L1 stabilization in breast cancer.

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Acknowledgements

X.H. would like to express deepest thanks to Guido Kroemer for the cancer immunity-associated technological training, ideological inspiration and moral edification in his laboratory. This work was supported by grants from the National Natural Science Foundation of China (31970696 and 81502975 to X.H. and 81830089 to T.L.), China Postdoctoral Science Foundation (2016T90413 and 2015M581693 to X.H.), SEU-Alphamab Joint Center (SA2015001 to X.H.), and Zhejiang Provincial Program for the Cultivation of High-level Innovative Health Talents (to X.B.).

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  1. These authors contributed equally: Xing Huang, Xiaozhen Zhang

Authors and Affiliations

  1. Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, School of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China

    Xing Huang, Xiaozhen Zhang, Xueli Bai & Tingbo Liang

  2. Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, Zhejiang, China

    Xing Huang, Xiaozhen Zhang, Xueli Bai & Tingbo Liang

  3. Innovation Center for the Study of Pancreatic Diseases, Zhejiang Province, Hangzhou, 310003, Zhejiang, China

    Xing Huang, Xiaozhen Zhang, Xueli Bai & Tingbo Liang

Authors
  1. Xing Huang
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Contributions

T.L., X.B. and X.H. conceived the correspondence. X.H. and X.Z. wrote and revised the paper, and T.L. and X.B. discussed and commented on the paper.

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Correspondence to Xueli Bai.

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Huang, X., Zhang, X., Bai, X. et al. Blocking PD-L1 for anti-liver cancer immunity: USP22 represents a critical cotarget. Cell Mol Immunol 17, 677–679 (2020). https://doi.org/10.1038/s41423-019-0348-4

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