Suppressive IL-17A+Foxp3+ and ex-Th17 IL-17AnegFoxp3+ Treg cells are a source of tumour-associated Treg cells

Th17 and regulatory T (T reg ) cells are integral in maintaining immune homeostasis and Th17–T reg imbalance is associated with inflammatory immunosuppression in cancer. Here we show that Th17 cells are a source of tumour-induced Foxp3 + cells. In addition to natural (n)T reg and induced (i)T reg cells that develop from naive precursors, suppressive IL-17A + Foxp3 + and ex-Th17 Foxp3 + cells are converted from IL-17A + Foxp3 neg cells in tumour-bearing mice. Metabolic phenotyping of Foxp3-expressing IL-17A + , ex-Th17 and iT reg cells demonstrates the dissociation between the metabolic fitness and the suppressive function of Foxp3-expressing T reg cell subsets. Although all Foxp3-expressing subsets are immunosuppressive, glycolysis is a prominent metabolic pathway exerted only by IL-17A + Foxp3 + cells. Transcriptome analysis and flow cytometry of IL-17A + Foxp3 + cells indicate that Folr4, GARP, Itgb8, Pglyrp1, Il1rl1, Itgae, TIGIT and ICOS are Th17-to-T reg cell transdifferentiation-associated markers. Tumour-associated Th17-to-T reg cell conversion identified here provides insights for targeting the dynamism of Th17–T reg cells in cancer immunotherapy.