title: Enrichment of regulatory T cells in invasive breast tumor correlates with the upregulation of IL-17A expression and invasiveness of the tumor.
abstract: Breast cancer is a leading cause of neoplasia-associated death in women worldwide. Regulatory T (Treg) and Th17 cells are enriched within some tumors, but the role these cells play in invasive ductal carcinoma (IDC) of the breast is unknown. We show that CD25(+) CD4(+) T cells from PBMCs and tumor express high levels of Foxp3, GITR, CTLA-4, and CD103, indicating that tumor-infiltrating Treg cells are functional and possibly recruited by CCL22. Additionally, we observed upregulation of Th17-related molecules (IL-17A, RORC, and CCR6) and IL-17A produced by tumor-infiltrating CD4(+) and CD8(+) T lymphocytes. The angiogenic factors CXCL8, MMP-2, MMP-9, and vascular endothelial growth factor detected within the tumor are possibly induced by IL-17 and indicative of poor disease prognosis. Treg and Th17 cells were synchronically increased in IDC patients, with positive correlation between Foxp3, IL-17A, and RORC expression, and associated with tumor aggressiveness. Therefore, Treg and Th17 cells can affect disease progression by Treg-cell-mediated suppression of the effector T-cell response, as indicated by a decrease in the proliferation of T cells isolated from PBMCs of IDC patients and induction of angiogenic factors by IL-17-producing Th17. The understanding of regulation of the Treg/Th17 axis may result in novel perspectives for the control of invasive tumors.
authors.affiliation: Department of Biochemistry and Immunology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil.
authors.forename: Luciana
authors.initials: L
authors.lastname: Benevides
authors.forename: Cristina R B
authors.initials: CR
authors.lastname: Cardoso
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Tiezzi
authors.forename: Heitor R C
authors.initials: HR
authors.lastname: Marana
authors.forename: Jurandyr M
authors.initials: JM
authors.lastname: Andrade
authors.forename: João S
authors.initials: JS
authors.lastname: Silva
mesh_terms: D015703:Antigens, CD / Q000378:metabolism; D001943:Breast Neoplasms / Q000276:immunology* / Q000473:pathology; D044584:Carcinoma, Ductal / Q000276:immunology* / Q000473:pathology; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000276:immunology; D054422:Chemokine CCL22 / Q000378:metabolism; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D053450:Glucocorticoid-Induced TNFR-Related Protein / Q000378:metabolism; D006801:Humans; D020381:Interleukin-17 / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000378:metabolism; D054399:Receptors, CCR6 / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
chemical_list: D015703:Antigens, CD; C106311:CCR6 protein, human; D054422:Chemokine CCL22; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D053450:Glucocorticoid-Induced TNFR-Related Protein; D020381:Interleukin-17; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; C539900:RORC protein, human; D054399:Receptors, CCR6; C491405:TNFRSF18 protein, human