Interferon-γ induces tumor resistance to anti-PD-1 immunotherapy by promoting YAP phase separation

• Published in: Molecular cell Vol. 81; no. 6; pp. 1216 - 1230.e9
• Main Authors: Yu, Man, Peng, Zhengxin, Qin, Min, Liu, Yang, Wang, Jingning, Zhang, Cai, Lin, Jiaming, Dong, Tianqi, Wang, Lulu, Li, Shasha, Yang, Yongqin, Xu, Shan, Guo, Wencong, Zhang, Xiao, Shi, Mingjun, Peng, Huiming, Luo, Xianwen, Zhang, Huixia, Zhang, Li, Li, Yan, Yang, Xiang-Ping, Sun, Shuguo
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 18-03-2021
• Subjects: A549 Cells; Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Animals; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Drug Resistance, Neoplasm - drug effects; Drug Resistance, Neoplasm - genetics; HEK293 Cells; Hippo pathway; Humans; IFN-gamma; Immune Checkpoint Inhibitors - pharmacology; Immunotherapy; Interferon-gamma - genetics; Interferon-gamma - metabolism; Mice; Mice, Knockout; Neoplasms, Experimental - genetics; Neoplasms, Experimental - metabolism; Neoplasms, Experimental - pathology; Neoplasms, Experimental - therapy; PD-1/PD-L1; phase separation; Programmed Cell Death 1 Receptor - antagonists & inhibitors; Programmed Cell Death 1 Receptor - genetics; Programmed Cell Death 1 Receptor - metabolism; Transcription Factors - genetics; Transcription Factors - metabolism; transcriptional control; tumor immunoterapy; YAP; phase separation; Hippo pathway; tumor immunoterapy; transcriptional control; IFN-gamma; PD-1/PD-L1; YAP
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2021.01.010

Interferon-γ (IFN-γ)-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-γ 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-γ 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.
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•IFN-γ promotes tumor cell YAP condensation after anti-PD-1 therapy•Hydrophobic interactions mediated by the coiled-coil domain initiate YAP condensation•YAP condensates form a transcription hub to maximize target gene expression•YAP phase separation mediates anti-PD-1 immunotherapy resistance
Cancer patients often develop adaptive resistance to aPD-1 therapy with an unclear mechanism. Yu et al. found that aPD-1 therapy induces IFN-γ-induced tumor cell YAP condensation, which mediates adaptive resistance of tumor cells by forming a transcription hub to enhance key immunosuppressive target gene expression.