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

Stephanie Downs-Canner, Sara Berkey, Greg M. Delgoffe, Robert P. Edwards, Tyler Curiel, Kunle Odunsi, David L. Bartlett and Nataša Obermajer ()
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Stephanie Downs-Canner: University of Pittsburgh
Sara Berkey: University of Pittsburgh
Greg M. Delgoffe: University of Pittsburgh Cancer Institute
Robert P. Edwards: University of Pittsburgh Cancer Institute
Tyler Curiel: UT Health Science Center at San Antonio
Kunle Odunsi: Roswell Park Cancer Institute
David L. Bartlett: University of Pittsburgh
Nataša Obermajer: University of Pittsburgh

Nature Communications, 2017, vol. 8, issue 1, 1-15

Abstract: Abstract Th17 and regulatory T (Treg) cells are integral in maintaining immune homeostasis and Th17–Treg 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)Treg and induced (i)Treg cells that develop from naive precursors, suppressive IL-17A+Foxp3+ and ex-Th17 Foxp3+ cells are converted from IL-17A+Foxp3neg cells in tumour-bearing mice. Metabolic phenotyping of Foxp3-expressing IL-17A+, ex-Th17 and iTreg cells demonstrates the dissociation between the metabolic fitness and the suppressive function of Foxp3-expressing Treg 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-Treg cell transdifferentiation-associated markers. Tumour-associated Th17-to-Treg cell conversion identified here provides insights for targeting the dynamism of Th17–Treg cells in cancer immunotherapy.

Date: 2017
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DOI: 10.1038/ncomms14649

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