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

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.