Many cancers evade immune surveillance by overexpressing PD-L1. PD-L1 interacted with its receptor PD-1, resulting in reduction of T cell proliferation and activation and thereafter cancer cell death mediated by T-lymphocyte. Understanding the mechanisms that regulate PD-L1 was of vital importance for immune checkpoint blockade therapy (ICBT). Human non-small cell lung cancer cells and 293FT cells were used to investigate the function of USP22 upon PD-L1 and CSN5 by WB, Immunoprecipitation, Immunofluorescence and Flow cytometry analysis. B16-F10 cells were used to explore the role of USP22 on tumorigenesis and T cell cytotoxicity. The relationship between USP22 and PD-L1 expression was investigated by Immunohistochemistry analysis in human non-small cell lung cancer samples. Our data showed that USP22 interacted with PD-L1 and promoted its stability. USP22 deubiquitinated PD-L1 and inhibited its proteasome degradation. Moreover, USP22 also interacted with CSN5 and stabilized CSN5 through deubiquitination. Either USP22 or CSN5 could facilitate the interaction of PD-L1 with the other one. Furthermore, USP22 removed K6, K11, K27, K29, K33 and K63-linked ubiquitin chain of both CSN5 and PD-L1. In addition, USP22 depletion inhibited tumorigenesis and promoted T cell cytotoxicity. Besides, USP22 expression positively correlated with PD-L1 expression in human non-small cell lung cancer samples. Here, we suggested that USP22 is a new regulator for PD-L1. On the one hand, USP22 could directly regulate PD-L1 stability through deubiquitination. On the other hand, USP22 regulated PD-L1 protein level through USP22-CSN5-PD-L1 axis. In addition, USP22 depletion inhibited tumorigenesis and promoted T cell cytotoxicity. Besides, USP22 expression positively correlated with PD-L1 expression in human non-small cell lung cancer samples. Together, we identified a new regulator of PD-L1 and characterized the important role of USP22 in PD-L1 mediated immune evasion. Targeting USP22 might be a new solution to ICBT.

中文翻译：

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去泛素化酶 USP22 调节人类癌细胞中的 PD-L1 降解。

许多癌症通过过度表达 PD-L1 来逃避免疫监视。PD-L1 与其受体 PD-1 相互作用，导致 T 细胞增殖和活化减少，随后由 T 淋巴细胞介导的癌细胞死亡。了解调节 PD-L1 的机制对于免疫检查点阻断疗法 (ICBT) 至关重要。通过WB、免疫沉淀、免疫荧光和流式细胞术分析，使用人非小细胞肺癌细胞和293FT细胞研究USP22对PD-L1和CSN5的作用。B16-F10 细胞用于探索 USP22 在肿瘤发生和 T 细胞细胞毒性中的作用。USP22 和 PD-L1 表达之间的关系通过免疫组织化学分析在人类非小细胞肺癌样本中进行研究。我们的数据显示 USP22 与 PD-L1 相互作用并促进其稳定性。USP22 去泛素化 PD-L1 并抑制其蛋白酶体降解。此外，USP22 还与 CSN5 相互作用并通过去泛素化稳定 CSN5。USP22 或 CSN5 都可以促进 PD-L1 与另一个的相互作用。此外，USP22 去除了 CSN5 和 PD-L1 的 K6、K11、K27、K29、K33 和 K63 连接的泛素链。此外，USP22 耗竭抑制了肿瘤发生并促进了 T 细胞的细胞毒性。此外，在人类非小细胞肺癌样本中，USP22 表达与 PD-L1 表达呈正相关。在这里，我们建议 USP22 是 PD-L1 的新调节剂。一方面，USP22可以通过去泛素化直接调节PD-L1的稳定性。另一方面，USP22通过USP22-CSN5-PD-L1轴调节PD-L1蛋白水平。此外，USP22 耗竭抑制了肿瘤发生并促进了 T 细胞的细胞毒性。此外，在人类非小细胞肺癌样本中，USP22 表达与 PD-L1 表达呈正相关。我们一起确定了一种新的 PD-L1 调节剂，并描述了 USP22 在 PD-L1 介导的免疫逃避中的重要作用。针对 USP22 可能是 ICBT 的新解决方案。