Chen Lei-Lei, Smith Matthew D, Lv Lei, Nakagawa Tadashi, Li Zhijun, Sun Shao-Cong, Brown Nicholas G, Xiong Yue, Xu Yan-Ping
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Sci Adv. 2020 Sep 18;6(38). doi: 10.1126/sciadv.abc9730. Print 2020 Sep.
TET2 DNA dioxygenase is frequently mutated in human hematopoietic malignancies and functionally inactivated in many solid tumors through a nonmutational mechanism. We recently found that TET2 mediates the interferon-JAK-STAT pathway to stimulate chemokine expression and tumor infiltration of lymphocytes (TILs). TET2 is monoubiquitylated at K1299, which promotes its activity. Here, we report that USP15 is a TET2 deubiquitinase and inhibitor. USP15 catalyzes the removal of K1299-linked monoubiquitin and negatively regulates TET2 activity. Gene expression profiling demonstrates that TET2 and USP15 oppositely regulate genes involved in multiple inflammatory pathways, and TET2 is a major target of USP15 function. Deletion of in melanoma stimulates chemokine expression and TILs in a TET2-dependent manner, leading to increased response to immunotherapy and extended life span of tumor-bearing mice. These results reveal a previously unknown regulator of TET2 activity and suggest USP15 as a potential therapeutic target for immunotherapy of solid tumors.
TET2 DNA双加氧酶在人类造血系统恶性肿瘤中经常发生突变,并且在许多实体瘤中通过非突变机制功能失活。我们最近发现,TET2介导干扰素-JAK-STAT途径以刺激趋化因子表达和淋巴细胞(TILs)的肿瘤浸润。TET2在K1299位点发生单泛素化,这促进了其活性。在此,我们报告USP15是一种TET2去泛素化酶和抑制剂。USP15催化去除与K1299相连的单泛素,并负向调节TET2活性。基因表达谱分析表明,TET2和USP15对参与多种炎症途径的基因具有相反的调节作用,并且TET2是USP15功能的主要靶点。在黑色素瘤中缺失 以TET2依赖的方式刺激趋化因子表达和TILs,导致对免疫治疗的反应增加以及荷瘤小鼠寿命延长。这些结果揭示了一种先前未知的TET2活性调节因子,并表明USP15作为实体瘤免疫治疗的潜在治疗靶点。 (注:原文中“Deletion of in melanoma”此处有缺失信息未完整表述)