Interferon-γ induces tumor resistance to anti-PD-1 immunotherapy by promoting YAP phase separation
Interferon-γ induces tumor resistance to anti-PD-1 immunotherapy by promoting YAP phase separation
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DOI：
10.1016/j.molcel.2021.01.010
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发表时间：
2021-03-18
期刊：
影响因子：
16
通讯作者：
Sun, Shuguo
中科院分区：
文献类型：
--
作者：
Yu, Man;Peng, Zhengxin;Sun, Shuguo
干扰素-γ介导的适应性耐药是提高实体瘤免疫治疗水平的主要障碍之一。然而，其机制尚不完全清楚。在这里，我们报告了干扰素-γ促进抗PD-1治疗后的YAP在肿瘤细胞中的核转位和时相分离。YAP螺旋线圈结构域的疏水相互作用介导液滴的起始，而C末端固有无序区域的弱相互作用促进液滴的形成。YAP与转录因子TEAD4、组蛋白乙酰转移酶EP300和介体1分开，形成转录中心，以最大化目标基因的转录，独立于规范的STAT1-IRF1转录程序。YAP时相分离的中断减少了肿瘤的生长，增强了免疫反应，并使肿瘤细胞对抗PD-1治疗敏感。YAP活性与患者预后呈负相关。我们的研究表明，YAP通过其核相分离介导了干扰素-γ的促肿瘤效应，提示YAP可以作为预测生物标志物和抗PD-1联合治疗的靶点。
Interferon-gamma (IFN-gamma)-mediated adaptive resistance is one major barrier to improving immunotherapy in solid tumors. However, the mechanisms are not completely understood. Here, we report that IFN-gamma promotes nuclear translocation and phase separation of YAP after anti-PD-1 therapy in tumor cells. Hydrophobic interactions of the YAP coiled-coil domain mediate droplet initiation, and weak interactions of the intrinsically disordered region in the C terminus promote droplet formation. YAP partitions with the transcription factor TEAD4, the histone acetyltransferase EP300, and Mediator1 and forms transcriptional hubs for maximizing target gene transcriptions, independent of the canonical STAT1-IRF1 transcription program. Disruption of YAP phase separation reduced tumor growth, enhanced immune response, and sensitized tumor cells to anti-PD-1 therapy. YAP activity is negatively correlated with patient outcome. Our study indicates that YAP mediates the IFN-gamma pro-tumor effect through its nuclear phase separation and suggests that YAP can be used as a predictive biomarker and target of anti-PD-1 combination therapy.