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
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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-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
