USP22 Deubiquitinates CD274 to Suppress Anticancer Immunity
USP22 Deubiquitinates CD274 to Suppress Anticancer Immunity
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USP22 去泛素化 CD274 以抑制抗癌免疫
DOI：
10.1158/2326-6066.cir-18-0910
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发表时间：
2019-10-01
影响因子：
10.1
通讯作者：
Bai, Xueli
中科院分区：
文献类型：
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作者：
Huang, Xing;Zhang, Qi;Bai, Xueli
CD274(PD-L1)抑制T细胞功能和抗肿瘤免疫反应。小鼠模型和人类数据集表明，CD274的表达受去泛素酶USP22控制，该酶限制免疫介导的肿瘤生长以及对免疫检查点阻断和化疗的反应。PD-1(CD279)-PD-L1(CD274)抑制信号在肿瘤免疫逃逸中起重要作用，已成为抗癌免疫治疗的主要靶点之一。有几项研究表明CD274的翻译后修饰在免疫失活和抑制方面具有强大的作用，如泛素化、磷酸化、糖基化和棕榈酰化。然而，CD274去泛素化的调控机制在很大程度上仍然不清楚。在此，我们确定泛素特异性蛋白水解酶22(USP22)是CD274的一种新的脱泛素酶。USP22直接与CD274的C末端相互作用，导致其去泛素化和稳定化。在多种癌症类型中，USP22在肝癌中高表达并频繁改变，与这些患者的预后不良密切相关。USP22基因缺失以免疫系统依赖的方式抑制肝癌生长，增加肿瘤免疫原性和肿瘤浸润性淋巴细胞，改善CD274靶向免疫治疗和以顺铂为基础的化疗的疗效。我们证明，靶向USP22是一种很有前途的策略，可以增强CD274扩增的癌症的抗癌免疫。
CD274 (PD-L1) inhibits T-cell function and antitumor immune responses. Mouse models and human datasets show that CD274 expression is controlled by the deubiquitinase USP22, which limits immune-mediated tumor growth and responses to immune checkpoint blockade and chemotherapy. PD-1 (CD279)–PD-L1 (CD274) inhibitory signaling is critical for cancer immune evasion, and thus has become one of the major targets in anticancer immunotherapy. There are several studies that demonstrate the potent effects of posttranslational modifications of CD274 on immune inactivation and suppression, such as ubiquitination, phosphorylation, glycosylation, and palmitoylation. However, the regulatory mechanisms for CD274 deubiquitination are still largely unclear. Here, we identified ubiquitin-specific protease 22 (USP22) as a novel deubiquitinase of CD274. USP22 directly interacted with the C terminus of CD274, inducing its deubiquitination and stabilization. Across multiple cancer types, USP22 was highly expressed and frequently altered in liver cancer, closely correlating with poor prognosis of these patients. Genetic depletion of USP22 inhibited liver cancer growth in an immune system–dependent manner, increased tumor immunogenicity and tumor-infiltrating lymphocytes, and improved therapeutic efficacy of CD274-targeted immunotherapy and CDDP-based chemotherapy in mice. We demonstrate that targeting USP22 is a promising strategy to potentiate anticancer immunity for CD274-amplified cancer.