刺
蛋白磷酸酶2
癌症研究
干扰素基因刺激剂
肿瘤微环境
信号转导
脱磷
巨噬细胞
免疫学
生物
磷酸化
免疫系统
细胞生物学
磷酸酶
先天免疫系统
体外
生物化学
航空航天工程
工程类
作者
Winson S. Ho,Isha Mondal,Beisi Xu,Oishika Das,Raymond Wai‐Yin Sun,Pochin Chiou,Xiaomin Cai,Foozhan Tahmasebinia,Elizabeth McFadden,Caren Yu-Ju Wu,Zhihao Wu,William Matsui,Michael Lim,Zhipeng Meng,Rongze Lu
摘要
Stimulator of IFN genes type I (STING-Type I) IFN signaling in myeloid cells plays a critical role in effective antitumor immune responses, but STING agonists as monotherapy have shown limited efficacy in clinical trials. The mechanisms that downregulate STING signaling are not fully understood. Here, we report that protein phosphatase 2A (PP2A), with its specific B regulatory subunit Striatin 4 (STRN4), negatively regulated STING-Type I IFN in macrophages. Mice with macrophage PP2A deficiency exhibited reduced tumor progression. The tumor microenvironment showed decreased immunosuppressive and increased IFN-activated macrophages and CD8+ T cells. Mechanistically, we demonstrated that Hippo kinase MST1/2 was required for STING activation. STING agonists induced dissociation of PP2A from MST1/2 in normal macrophages, but not in tumor conditioned macrophages. Furthermore, our data showed that STRN4 mediated PP2A binding to and dephosphorylation of Hippo kinase MST1/2, resulting in stabilization of YAP/TAZ to antagonize STING activation. In human patients with glioblastoma (GBM), YAP/TAZ was highly expressed in tumor-associated macrophages but not in nontumor macrophages. We also demonstrated that PP2A/STRN4 deficiency in macrophages reduced YAP/TAZ expression and sensitized tumor-conditioned macrophages to STING stimulation. In summary, we demonstrated that PP2A/STRN4-YAP/TAZ has, in our opinion, been an unappreciated mechanism that mediates immunosuppression in tumor-associated macrophages, and targeting the PP2A/STRN4-YAP/TAZ axis can sensitize tumors to immunotherapy.
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