IL-27 confers a protumorigenic activity of regulatory T cells via CD39
Menée in vitro et à l'aide de modèles murins, cette étude met en évidence un mécanisme par lequel l'interleukine IL-27, en induisant l'expression de l'ectonucléotidase CD39, favorise l'activité protumorigène des lymphocytes T régulateurs
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.Expression of ectonucleotidase CD39 contributes to the suppressive activity of Foxp3+ regulatory T cells (Tregs) by hydrolyzing immunogenic ATP into AMP. The molecular mechanism that drives CD39 expression on Tregs remains elusive. We found that tumor-infiltrating Tregs (Ti-Tregs) failed to up-regulate CD39 in mice lacking EBI3 subunit of IL-27 or IL-27Ra. Mixed bone marrow chimera and in vitro studies showed that IL-27 signaling in Tregs directly drives CD39 expression on Ti-Tregs in a STAT1-dependent, but STAT3- and T-bet–independent, manner. Tregs stimulated with IL-27 showed enhanced suppressive activities against CD8+ T cell responses in vitro. Moreover, IL-27Ra–deficient Tregs and STAT1-deficient Tregs were less efficient than WT Tregs in suppressing antitumor immunity in vivo. CD39 inhibition significantly abolished IL-27–induced suppressive activities of Tregs. Thus, IL-27 signaling in Tregs critically contributes to protumorigenic properties of Tregs via up-regulation of CD39.