title: Breast cancer-derived transforming growth factor-β and tumor necrosis factor-α compromise interferon-α production by tumor-associated plasmacytoid dendritic cells.
abstract: 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.
authors: Université de Lyon, Lyon, France.
authors: Vanja
authors: V
authors: Sisirak
authors: Nelly
authors: N
authors: Vey
authors: Nadège
authors: N
authors: Goutagny
authors: Sarah
authors: S
authors: Renaudineau
authors: Marine
authors: M
authors: Malfroy
authors: Sandra
authors: S
authors: Thys
authors: Isabelle
authors: I
authors: Treilleux
authors: Sana Intidhar
authors: SI
authors: Labidi-Galy
authors: Thomas
authors: T
authors: Bachelot
authors: Colette
authors: C
authors: Dezutter-Dambuyant
authors: Christine
authors: C
authors: Ménétrier-Caux
authors: Jean-Yves
authors: JY
authors: Blay
authors: Christophe
authors: C
authors: Caux
authors: Nathalie
authors: N
authors: Bendriss-Vermare
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism*; D054405:Chemokine CCL3 / Q000096:biosynthesis; D054357:Chemokine CXCL10 / Q000096:biosynthesis; D003713:Dendritic Cells / Q000378:metabolism*; D005260:Female; D006801:Humans; D050839:Interferon Regulatory Factor-7 / Q000096:biosynthesis; D016898:Interferon-alpha / Q000096:biosynthesis*; D016899:Interferon-beta / Q000096:biosynthesis; D010766:Phosphorylation; D021381:Protein Transport; D011994:Recombinant Proteins / Q000494:pharmacology; D051899:Smad2 Protein / Q000378:metabolism; D051199:Toll-Like Receptor 7 / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000378:metabolism / Q000494:pharmacology*
chemical_list: C515429:CCL3 protein, human; C114753:CXCL10 protein, human; D054405:Chemokine CCL3; D054357:Chemokine CXCL10; D050839:Interferon Regulatory Factor-7; D016898:Interferon-alpha; D011994:Recombinant Proteins; C497782:SMAD2 protein, human; D051899:Smad2 Protein; C495348:TLR7 protein, human; C495371:TLR9 protein, human; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D016899:Interferon-beta