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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenocarcinoma, Clear Cell / immunology*
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Adult
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Aged
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Aged, 80 and over
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Animals
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Antigens, CD / metabolism
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Cell Line, Tumor
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Cell Transdifferentiation / immunology
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Cytokines / metabolism
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Female
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Flow Cytometry
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Forkhead Transcription Factors / metabolism
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Gene Expression Profiling
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Homeostasis / immunology
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Humans
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Immune Tolerance / immunology*
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Inducible T-Cell Co-Stimulator Protein / metabolism
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Inflammation / immunology
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Integrin alpha Chains / metabolism
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Integrin beta Chains / metabolism
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Interleukin-1 Receptor-Like 1 Protein / metabolism
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Interleukin-17 / metabolism
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Lymphocytes, Tumor-Infiltrating / immunology
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Membrane Proteins / metabolism
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Mice, Knockout
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Middle Aged
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Neoplasms, Cystic, Mucinous, and Serous / immunology*
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Nuclear Receptor Subfamily 1, Group F, Member 3 / genetics
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Ovarian Neoplasms / immunology*
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Phenotype
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Receptors, Cell Surface / metabolism
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Receptors, Immunologic / metabolism
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T-Lymphocyte Subsets
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T-Lymphocytes, Regulatory / immunology*
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Th17 Cells / immunology*
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Tumor Microenvironment / immunology*
Substances
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Antigens, CD
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Cytokines
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Forkhead Transcription Factors
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Foxp3 protein, mouse
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Icos protein, mouse
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Il17a protein, mouse
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Il1rl1 protein, mouse
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Inducible T-Cell Co-Stimulator Protein
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Integrin alpha Chains
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Integrin beta Chains
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Interleukin-1 Receptor-Like 1 Protein
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Interleukin-17
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Lrrc32 protein, mouse
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Membrane Proteins
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Nuclear Receptor Subfamily 1, Group F, Member 3
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Pglyrp1 protein, mouse
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Receptors, Cell Surface
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Receptors, Immunologic
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Rorc protein, mouse
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T cell Ig and ITIM domain protein, mouse
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alpha E integrins
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folate receptor 4, mouse
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integrin beta8