Breast cancer-derived transforming growth factor-β and tumor necrosis factor-α compromise interferon-α production by tumor-associated plasmacytoid dendritic cells

Int J Cancer. 2013 Aug 1;133(3):771-8. doi: 10.1002/ijc.28072. Epub 2013 Mar 8.


We previously reported that plasmacytoid dendritic cells (pDCs) infiltrating breast tumors are impaired for their interferon-α (IFN-α) production, resulting in local regulatory T cells amplification. We designed our study to decipher molecular mechanisms of such functional defect of tumor-associated pDC (TApDC) in breast cancer. We demonstrate that besides IFN-α, the production by Toll-like receptor (TLR)-activated healthy pDC of IFN-β and TNF-α but not IP-10/CXCL10 nor MIP1-α/CCL3 is impaired by the breast tumor environment. Importantly, we identified TGF-β and TNF-α as major soluble factors involved in TApDC functional alteration. Indeed, recombinant TGF-β1 and TNF-α synergistically blocked IFN-α production of TLR-activated pDC, and neutralization of TGF-β and TNF-α in tumor-derived supernatants restored pDCs' IFN-α production. The involvment of tumor-derived TGF-β was further confirmed in situ by the detection of phosphorylated Smad2 in the nuclei of TApDC in breast tumor tissues. Mechanisms of type I IFN inhibition did not involve TLR downregulation but the inhibition of IRF-7 expression and nuclear translocation in pDC after their exposure to tumor-derived supernatants or recombinant TGF-β1 and TNF-α. Our findings indicate that targeting TApDC to restore their IFN-α production might be an achievable strategy to induce antitumor immunity in breast cancer by combining TLR7/9-based immunotherapy with TGF-β and TNF-α antagonists.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Breast Neoplasms / metabolism*
  • Chemokine CCL3 / biosynthesis
  • Chemokine CXCL10 / biosynthesis
  • Dendritic Cells / metabolism*
  • Female
  • Humans
  • Interferon Regulatory Factor-7 / biosynthesis
  • Interferon-alpha / biosynthesis*
  • Interferon-beta / biosynthesis
  • Phosphorylation
  • Protein Transport
  • Recombinant Proteins / pharmacology
  • Smad2 Protein / metabolism
  • Toll-Like Receptor 7 / metabolism
  • Toll-Like Receptor 9 / metabolism
  • Transforming Growth Factor beta / metabolism
  • Transforming Growth Factor beta / pharmacology*
  • Tumor Necrosis Factor-alpha / biosynthesis
  • Tumor Necrosis Factor-alpha / metabolism
  • Tumor Necrosis Factor-alpha / pharmacology*


  • CCL3 protein, human
  • CXCL10 protein, human
  • Chemokine CCL3
  • Chemokine CXCL10
  • Interferon Regulatory Factor-7
  • Interferon-alpha
  • Recombinant Proteins
  • SMAD2 protein, human
  • Smad2 Protein
  • TLR7 protein, human
  • TLR9 protein, human
  • Toll-Like Receptor 7
  • Toll-Like Receptor 9
  • Transforming Growth Factor beta
  • Tumor Necrosis Factor-alpha
  • Interferon-beta