IL-27 confers a protumorigenic activity of regulatory T cells via CD39

Significance Regulatory T cells (Tregs) inhibit autoimmune responses and are essential for immune homeostasis. By contrast, in settings of cancerous inflammation, Tregs represent a strong protumorigenic immune cell population via the incapacitation of various tumoricidal immune cells. By using multiple gene-deficient mouse systems, we show that IL-27 specifically induces ectonucleotidase CD39 expression on tumor-infiltrating Tregs in a STAT1-dependent manner. Protumorigenic activity of Tregs is significantly ameliorated by inhibiting CD39. Lack of IL-27Ra prevents CD39 upregulation on Tregs, which rescues cytotoxic CD8 + T cells from Treg-mediated inhibition in tumor tissue. Our findings unveil a IL-27–STAT1–CD39 axis as a crucial mechanism for the protumorigenic function of Tregs. Targeting this new molecular pathway may facilitate the development of antitumor therapeutic approaches.