title: Suppressive IL-17A+Foxp3+and ex-Th17 IL-17AnegFoxp3+Tregcells are a source of tumour-associated Tregcells.
abstract: Th17 and regulatory T (Treg) cells are integral in maintaining immune homeostasis and Th17-Tregimbalance 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)Tregand induced (i)Tregcells that develop from naive precursors, suppressive IL-17A+Foxp3+and ex-Th17 Foxp3+cells are converted from IL-17A+Foxp3negcells in tumour-bearing mice. Metabolic phenotyping of Foxp3-expressing IL-17A+, ex-Th17 and iTregcells demonstrates the dissociation between the metabolic fitness and the suppressive function of Foxp3-expressing Tregcell 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-Tregcell transdifferentiation-associated markers. Tumour-associated Th17-to-Tregcell conversion identified here provides insights for targeting the dynamism of Th17-Tregcells in cancer immunotherapy.
authors.affiliation: Department of Surgical Oncology, University of Pittsburgh, 5150 Centre Avenue, Pittsburgh, Pennsylvania 15213, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Downs-Canner
authors.affiliation: Department of Surgical Oncology, University of Pittsburgh, 5150 Centre Avenue, Pittsburgh, Pennsylvania 15213, USA.
authors.forename: Sara
authors.initials: S
authors.lastname: Berkey
authors.affiliation: University of Pittsburgh Cancer Institute, 5150 Centre Avenue, Pittsburgh, Pennsylvania 15213, USA.|Tumour Microenvironment Center, Hillman Cancer Center, University of Pittsburgh, 5115 Centre Avenue, Pittsburgh, Pennsylvania 15213, USA.|Magee-Womens Research Institute Ovarian Cancer Center of Excellence, 5150 Centre Avenue, Pittsburgh, Pennsylvania 15213, USA.
authors.forename: Greg M
authors.initials: GM
authors.lastname: Delgoffe
authors.affiliation: University of Pittsburgh Cancer Institute, 5150 Centre Avenue, Pittsburgh, Pennsylvania 15213, USA.|Magee-Womens Research Institute Ovarian Cancer Center of Excellence, 5150 Centre Avenue, Pittsburgh, Pennsylvania 15213, USA.|Peritoneal/Ovarian Cancer Specialty Care Center, Pittsburgh, Pennsylvania 15213, USA.
authors.forename: Robert P
authors.initials: RP
authors.lastname: Edwards
authors.affiliation: UT Health Science Center at San Antonio, 8403 Floyd Curl Drive, San Antonio, Texas 78229, USA.
authors.forename: Tyler
authors.initials: T
authors.lastname: Curiel
authors.affiliation: Departments of Gynecologic Oncology and Immunology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, New York 14263, USA.
authors.forename: Kunle
authors.initials: K
authors.lastname: Odunsi
authors.affiliation: Department of Surgical Oncology, University of Pittsburgh, 5150 Centre Avenue, Pittsburgh, Pennsylvania 15213, USA.
authors.forename: David L
authors.initials: DL
authors.lastname: Bartlett
authors.affiliation: Department of Surgical Oncology, University of Pittsburgh, 5150 Centre Avenue, Pittsburgh, Pennsylvania 15213, USA.
authors.forename: Nataša
authors.initials: N
authors.lastname: Obermajer
mesh_terms: D018262:Adenocarcinoma, Clear Cell / Q000276:immunology*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D045744:Cell Line, Tumor; D054338:Cell Transdifferentiation / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000378:metabolism; D020869:Gene Expression Profiling; D006706:Homeostasis / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D060889:Inducible T-Cell Co-Stimulator Protein / Q000378:metabolism; D007249:Inflammation / Q000276:immunology; D039001:Integrin alpha Chains / Q000378:metabolism; D039641:Integrin beta Chains / Q000378:metabolism; D000072179:Interleukin-1 Receptor-Like 1 Protein / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D008565:Membrane Proteins / Q000378:metabolism; D018345:Mice, Knockout; D008875:Middle Aged; D018297:Neoplasms, Cystic, Mucinous, and Serous / Q000276:immunology*; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000235:genetics; D010051:Ovarian Neoplasms / Q000276:immunology*; D010641:Phenotype; D011956:Receptors, Cell Surface / Q000378:metabolism; D011971:Receptors, Immunologic / Q000378:metabolism; D016176:T-Lymphocyte Subsets; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology*; D059016:Tumor Microenvironment / Q000276:immunology*
chemical_list: D015703:Antigens, CD; D016207:Cytokines; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C556694:Icos protein, mouse; C098680:Il17a protein, mouse; C486189:Il1rl1 protein, mouse; D060889:Inducible T-Cell Co-Stimulator Protein; D039001:Integrin alpha Chains; D039641:Integrin beta Chains; D000072179:Interleukin-1 Receptor-Like 1 Protein; D020381:Interleukin-17; C484196:Lrrc32 protein, mouse; D008565:Membrane Proteins; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; C113582:Pglyrp1 protein, mouse; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; C539901:Rorc protein, mouse; C556305:T cell Ig and ITIM domain protein, mouse; C091367:alpha E integrins; C543634:folate receptor 4, mouse; C094865:integrin beta8