Suppressive IL-17A+ Foxp3+ and ex-Th17 IL-17Aneg Foxp3+ 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, Nataša Obermajer

Research output: Contribution to journalArticle

37 Scopus citations

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+ Foxp3 neg 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.

Original languageEnglish (US)
Article number14649
JournalNature communications
Volume8
DOIs
StatePublished - Mar 14 2017

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    Downs-Canner, S., Berkey, S., Delgoffe, G. M., Edwards, R. P., Curiel, T., Odunsi, K., Bartlett, D. L., & Obermajer, N. (2017). Suppressive IL-17A+ Foxp3+ and ex-Th17 IL-17Aneg Foxp3+ Treg cells are a source of tumour-associated Treg cells. Nature communications, 8, [14649]. https://doi.org/10.1038/ncomms14649