Zhang Lin, Yao Jun, Wei Yongkun, Zhou Zhifen, Li Ping, Qu Jingkun, Badu-Nkansah Akosua, Yuan Xiangliang, Huang Yu-Wen, Fukumura Kazutaka, Mao Xizeng, Chang Wei-Chao, Saunus Jodi, Lakhani Sunil, Huse Jason T, Hung Mien-Chie, Yu Dihua
Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX 77030, USA.
Sci Transl Med. 2020 May 27;12(545). doi: 10.1126/scitranslmed.aaz5387.
The functions of immune cells in brain metastases are unclear because the brain has traditionally been considered "immune privileged." However, we found that a subgroup of immunosuppressive neutrophils is recruited into the brain, enabling brain metastasis development. In brain metastatic cells, enhancer of zeste homolog 2 (EZH2) is highly expressed and phosphorylated at tyrosine-696 (pY696)-EZH2 by nuclear-localized Src tyrosine kinase. Phosphorylation of EZH2 at Y696 changes its binding preference from histone H3 to RNA polymerase II, which consequently switches EZH2's function from a methyltransferase to a transcription factor that increases expression. c-Jun up-regulates protumorigenic inflammatory cytokines, including granulocyte colony-stimulating factor (G-CSF), which recruits Arg1- and PD-L1 immunosuppressive neutrophils into the brain to drive metastasis outgrowth. G-CSF-blocking antibodies or immune checkpoint blockade therapies combined with Src inhibitors impeded brain metastasis in multiple mouse models. These findings indicate that pY696-EZH2 can function as a methyltransferase-independent transcription factor to facilitate the brain infiltration of immunosuppressive neutrophils, which could be clinically targeted for brain metastasis treatment.
免疫细胞在脑转移中的功能尚不清楚，因为传统上认为大脑具有“免疫特权”。然而，我们发现免疫抑制性中性粒细胞的一个亚群被招募到大脑中，从而促进脑转移的发展。在脑转移细胞中，zeste同源物2增强子（EZH2）高度表达，并被核定位的Src酪氨酸激酶磷酸化在酪氨酸696位点（pY696-EZH2）。EZH2在Y696位点的磷酸化改变了其从组蛋白H3到RNA聚合酶II的结合偏好，从而将EZH2的功能从甲基转移酶转变为增加表达的转录因子。c-Jun上调促肿瘤炎症细胞因子，包括粒细胞集落刺激因子（G-CSF），后者将精氨酸酶1和程序性死亡配体1（PD-L1）免疫抑制性中性粒细胞招募到大脑中以驱动转移灶生长。G-CSF阻断抗体或免疫检查点阻断疗法与Src抑制剂联合使用可在多种小鼠模型中阻碍脑转移。这些发现表明，pY696-EZH2可作为一种不依赖甲基转移酶的转录因子，促进免疫抑制性中性粒细胞的脑浸润，这在临床上可作为脑转移治疗的靶点。
