YAP is essential for treg-mediated suppression of antitumor immunity

Xuhao Ni, Jinhui Tao, Joseph Barbi, Qian Chen, Benjamin V. Park, Zhiguang Li, Nailing Zhang, Andriana Lebid, Anjali Ramaswamy, Ping Wei, Ying Zheng, Xuehong Zhang, Xingmei Wu, Paolo Vignali, Cui Ping Yang, Huabin Li, Drew Pardoll, Ling Lu, Duojia Pan, Fan Pan

Research output: Contribution to journalArticle

41 Scopus citations

Abstract

Regulatory T cells (Treg) are critical for maintaining self-tolerance and immune homeostasis, but their suppressive function can impede effective antitumor immune responses. FOXP3 is a transcription factor expressed in Tregs that is required for their function. However, the pathways and microenvironmental cues governing FOXP3 expression and Treg function are not completely understood. Herein, we report that YAP, a coactivator of the Hippo pathway, is highly expressed in Tregs and bolsters FOXP3 expression and Treg function in vitro and in vivo. This potentiation stemmed from YAP-dependent upregulation of activin signaling, which amplifies TGFβ/ SMAD activation in Tregs. YAP deficiency resulted in dysfunctional Tregs unable to suppress antitumor immunity or promote tumor growth in mice. Chemical YAP antagonism and knockout or blockade of the YAP-regulated activin receptor similarly improved antitumor immunity. Thus, we identify YAP as an unexpected amplifier of a Treg-reinforcing pathway with significant potential as an anticancer immunotherapeutic target. SIGnIFICAnCE: Tregs suppress antitumor immunity, and pathways supporting their function can be novel immunotherapy targets. Here, the selective expression of YAP by Tregs, its importance for their function, and its unexpected enhancement of pro-Treg Activin/SMAD signaling are reported, as are validations of potential cancer-fighting antagonists of YAP and its regulatory targets.

Original languageEnglish (US)
Pages (from-to)1026-1043
Number of pages18
JournalCancer discovery
Volume8
Issue number8
DOIs
StatePublished - Aug 2018

ASJC Scopus subject areas

  • Oncology

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  • Cite this

    Ni, X., Tao, J., Barbi, J., Chen, Q., Park, B. V., Li, Z., Zhang, N., Lebid, A., Ramaswamy, A., Wei, P., Zheng, Y., Zhang, X., Wu, X., Vignali, P., Yang, C. P., Li, H., Pardoll, D., Lu, L., Pan, D., & Pan, F. (2018). YAP is essential for treg-mediated suppression of antitumor immunity. Cancer discovery, 8(8), 1026-1043. https://doi.org/10.1158/2159-8290.CD-17-1124