Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
The Key Laboratory of Developmental Genes and Human Disease, Institute of Life Sciences, Southeast University, Nanjing, Jiangsu, China.
Cancer Immunol Res. 2019 Oct;7(10):1580-1590. doi: 10.1158/2326-6066.CIR-18-0910. Epub 2019 Aug 9.
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.
PD-1（CD279）-PD-L1（CD274）抑制信号对于癌症免疫逃逸至关重要，因此已成为抗癌免疫治疗的主要靶点之一。有几项研究表明 CD274 的翻译后修饰对免疫失活和抑制具有强大的作用，如泛素化、磷酸化、糖基化和棕榈酰化。然而，CD274 去泛素化的调节机制在很大程度上仍不清楚。在这里，我们鉴定了泛素特异性蛋白酶 22（USP22）是 CD274 的一种新型去泛素酶。USP22 直接与 CD274 的 C 末端相互作用，诱导其去泛素化和稳定。在多种癌症类型中，USP22 在肝癌中高度表达且经常发生改变，与这些患者的不良预后密切相关。USP22 的遗传耗竭以依赖于免疫系统的方式抑制肝癌生长，增加肿瘤免疫原性和肿瘤浸润淋巴细胞，并提高 CD274 靶向免疫疗法和 CDDP 为基础的化疗在小鼠中的治疗效果。我们证明，靶向 USP22 是增强 CD274 扩增癌症抗癌免疫的一种有前途的策略。
