Enrichment of regulatory T cells in invasive breast tumor correlates with the upregulation of IL-17A expression and invasiveness of the tumor

Eur J Immunol. 2013 Jun;43(6):1518-28. doi: 10.1002/eji.201242951. Epub 2013 May 16.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, CD / metabolism
  • Breast Neoplasms / immunology*
  • Breast Neoplasms / pathology
  • Carcinoma, Ductal / immunology*
  • Carcinoma, Ductal / pathology
  • Cell Proliferation
  • Cell Transformation, Neoplastic / immunology
  • Chemokine CCL22 / metabolism
  • Female
  • Forkhead Transcription Factors / metabolism
  • Glucocorticoid-Induced TNFR-Related Protein / metabolism
  • Humans
  • Interleukin-17 / genetics
  • Interleukin-17 / metabolism*
  • Neoplasm Invasiveness
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / metabolism
  • Receptors, CCR6 / metabolism
  • T-Lymphocytes, Regulatory / immunology*
  • Th17 Cells / immunology*
  • Tumor Cells, Cultured
  • Up-Regulation


  • Antigens, CD
  • CCR6 protein, human
  • Chemokine CCL22
  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • Glucocorticoid-Induced TNFR-Related Protein
  • Interleukin-17
  • Nuclear Receptor Subfamily 1, Group F, Member 3
  • RORC protein, human
  • Receptors, CCR6
  • TNFRSF18 protein, human