期刊
INTERNATIONAL JOURNAL OF CANCER
卷 133, 期 3, 页码 771-778出版社
WILEY-BLACKWELL
DOI: 10.1002/ijc.28072
关键词
plasmacytoid dendritic cells; breast cancer; type I IFNs; TGF-; TLR ligands
类别
资金
- Breast Cancer Research Fundation [4832]
- Association pour la Recherche sur le Cancer (ARC) [7896]
- Comite departemental de Saone-et-Loire et du Rhone de la Ligue contre le Cancer
- Lyon Biopole DEMINAP
- PLATINE
- Institut National du Cancer [ACI-63-04, ACI 2007-2009, Met-escape 2007, Breast-Immune 2009]
- Region Rhone-Alpes
We previously reported that plasmacytoid dendritic cells (pDCs) infiltrating breast tumors are impaired for their interferon- (IFN-) 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-, the production by Toll-like receptor (TLR)-activated healthy pDC of IFN- and TNF- but not IP-10/CXCL10 nor MIP1-/CCL3 is impaired by the breast tumor environment. Importantly, we identified TGF- and TNF- as major soluble factors involved in TApDC functional alteration. Indeed, recombinant TGF-1 and TNF- synergistically blocked IFN- production of TLR-activated pDC, and neutralization of TGF- and TNF- in tumor-derived supernatants restored pDCs' IFN- production. The involvment of tumor-derived TGF- 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-1 and TNF-. Our findings indicate that targeting TApDC to restore their IFN- production might be an achievable strategy to induce antitumor immunity in breast cancer by combining TLR7/9-based immunotherapy with TGF- and TNF- antagonists.
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