Forkhead box protein P3 (FOXP3) is a crucial regulator of regulatory T (T_reg) cell gene expression that is responsible for much of the suppressive potential displayed by these cells. The regulation of FOXP3 expression in T_reg cells occurs through the concerted action of transcription factors and extensive epigenetic control mechanisms; furthermore, post-translational modifications are also capable of modulating FOXP3 function. These several layers of FOXP3 control are responsive to positive and negative regulation by factors in the tissue environment, including cytokines, inflammatory mediators and metabolic factors. Modulating FOXP3 expression and T_reg cell function by targeting newly discovered regulatory nodes may lead to the development of new immunotherapies for cancer and autoimmune diseases.

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. Cancer Discov; 8(8); 1026–43. ©2018 AACR. This article is highlighted in the In This Issue feature, p. 899