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.