Gregory Shana, Xu Yanan, Xie Ping, Fan Jie, Gao Beixue, Mani Nikita, Iyer Radhika, Tang Amy, Wei Juncheng, Chaudhuri Shuvam Mohan, Wang Shengnan, Liu Huiping, Zhang Bin, Fang Deyu
Department of Pathology, Northwestern University Feinberg School of Medicine 303 E. Chicago Ave, Chicago, IL 60611, USA.
Department of Medicine (Hematology and Oncology), Northwestern University Feinberg School of Medicine 303 E. Chicago Ave, Chicago, IL 60611, USA.
Am J Cancer Res. 2022 Dec 15;12(12):5564-5575. eCollection 2022.
Cancer cells evade the immune system by expressing inhibitory immune checkpoint receptors such as ecto-5'-nucleotidase (NT5E), also known as CD73, which consequently suppress tumor neoantigen-specific immune response. Blockade of CD73 in mouse models of breast cancer showed a reduction in tumor growth and metastasis. CD73 expression is elevated in a variety of human tumors including breast cancer. While the regulation of CD73 expression at the transcriptional level has been well understood, the factors involved in regulating CD73 expression at the post-transcriptional level have not been identified. Herein, we discovered that the ubiquitin-specific peptidase 22 (USP22), a deubiquitinase associated with poor prognosis and overexpressed in breast cancers, is a positive regulator for CD73. Targeted USP22 deletion resulted in a statistically significant reduction in CD73 protein expression. In contrast, CD73 mRNA expression levels were not reduced, but even slightly increased by USP22 deletion. Further analysis demonstrated that USP22 is a deubiquitinase that specifically interacts with and inhibits CD73 ubiquitination. Consequently, USP22 protects CD73 from ubiquitin-mediated proteasomal degradation in breast cancer cells. Targeted USP22 deletion, inhibits syngeneic breast cancer growth. Collectively, our study reveals USP22 as a positive regulator to promote CD73 expression in breast cancer and provides a rationale to target USP22 in antitumor immune therapy.
癌细胞通过表达抑制性免疫检查点受体来逃避免疫系统，例如胞外5'-核苷酸酶（NT5E），也称为CD73，其结果是抑制肿瘤新抗原特异性免疫反应。在乳腺癌小鼠模型中阻断CD73可使肿瘤生长和转移减少。CD73在包括乳腺癌在内的多种人类肿瘤中表达升高。虽然在转录水平上对CD73表达的调控已得到充分了解，但在转录后水平上参与调控CD73表达的因素尚未确定。在此，我们发现泛素特异性肽酶22（USP22），一种与预后不良相关且在乳腺癌中过表达的去泛素化酶，是CD73的正向调节因子。靶向删除USP22导致CD73蛋白表达在统计学上显著降低。相反，CD73 mRNA表达水平并未降低，反而因USP22的缺失而略有增加。进一步分析表明，USP22是一种去泛素化酶，它特异性地与CD73相互作用并抑制其泛素化。因此，USP22保护CD73免受乳腺癌细胞中泛素介导的蛋白酶体降解。靶向删除USP22可抑制同基因乳腺癌的生长。总的来说，我们的研究揭示了USP22作为促进乳腺癌中CD73表达的正向调节因子，并为在抗肿瘤免疫治疗中靶向USP22提供了理论依据。
