Interferon-g induces tumor resistance to anti-PD-1 immunotherapy by promoting YAP phase separation
Interferon-g induces tumor resistance to anti-PD-1 immunotherapy by promoting YAP phase separation
复制标题
干扰素-g 通过促进 YAP 相分离诱导肿瘤对抗 PD-1 免疫疗法的抵抗
作者：
Man Yu;Zhengxin Peng;Min Qin;Yang Liu;Jingning Wang;Cai Zhang;Jiaming Lin;Tianqi Dong;Lulu Wang;Shasha Li;Yongqin Yang;Shan Xu;Wencong Guo;Xiao Zhang;MIngjun Shi;Huiming Peng;Xianwen Luo;Huixia Zhang;Li Zhang;Yan Li;Xiang-Ping Yang;Shuguo Sun
IFN-γ介导的适应性抵抗是提高实体瘤免疫治疗的主要障碍之一。然而，其机制并不完全清楚。在这里，我们报告了IFN-g促进肿瘤细胞中抗PD-1治疗后雅普的核转位和相分离。雅普卷曲螺旋结构域的疏水相互作用介导液滴的起始，并且C末端的固有无序区域的弱相互作用促进液滴的形成。雅普与转录因子TEAD 4、组蛋白乙酰转移酶EP 300和Mediator 1一起分配，并形成转录枢纽以最大化靶基因的转录，而不依赖于典型的STAT 1-IRF 1转录程序。雅普相分离的破坏减少了肿瘤生长，增强了免疫应答，并使肿瘤细胞对抗PD-1治疗敏感。雅普活性与患者预后呈负相关。我们的研究表明，雅普通过其核相分离介导IFN-g的促肿瘤效应，并表明雅普可用作预测生物标志物和抗PD-1联合治疗的靶点
IFN-g mediated adaptive resistance is one of major barrier to improve immunotherapy in solid tumors. However, the mechanisms are not completely understood. Here, we report that IFN-g promotes nuclear translocation and phase separation of YAP after anti-PD-1 therapy in tumor cells. Hydrophobic interactions of YAP Coiled Coil domain mediate droplets initiation and weak interactions of the intrinsically disordered region in C terminus promote droplet formation. YAP partitions with the transcription factor TEAD4, histone acetyltransferase EP300, and Mediator1 and forms transcriptional hubs for maximizing target gene transcriptions, independent of 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 IFN-g pro-tumor effect through its nuclear phase separation and suggests that YAP can be used as a predictive biomarker and a target of anti-PD-1 combination therapy