Conventional dendritic cell and plasmacytoid dendritic cell (pDC) subsets have specialized functions that can be modulated by the tumor microenvironment, and produce different interferons that are central to antitumor immune responses. While the function of type I interferons in tumor immunity is well characterized, that of type III interferons produced by type 1 conventional dendritic cells in the tumor microenvironment remains unclear. Here we demonstrate in vitro that type III interferons orchestrate pDC survival, activation and TLR7 expression in the blood, thereby enhancing pDC responses to a TLR7 ligand. Moreover, we show that tumor-associated pDCs express the highest level of IFNLR1, and that these immune cell subsets are the most responsive to IFN-III. Importantly, type III interferons prevent the inhibition of pDCs induced by TGF-β or PGE2 in tumor soluble milieu from patients to restores production of IFN-α in pDCs. With TGF-β or PGE2 having pleotropic functions in immune regulation, our results thus implicate IFN-III-mediated immune modulation to have broad impact on various pathological situations.

pDCs can be distinguished from conventional dendritic cells (cDC) by their lack of CD11c and the surface expression of BDCA2/CD303 and IL-3 Receptor (CD123). Their main function is to produce high amounts of type I interferon (IFN-I) after TLR7 or TLR9 engagement by viral ssRNA and ODNs CpG, respectively 1,2 . IFN-I produced by pDCs was shown to induce antiviral and antitumor responses in epithelial cells and immune cells 3,4 , which has led to the approval of IFN-I derivatives, namely IFN-α2 A and IFN-α2B, as treatments for several malignancies 5 . In cancer, an IFN-I signature in the tumor microenvironment (TME) was correlated with "hot tumors", characterized by a strong immune infiltrate and a better response to immunotherapies 6 . Conversely, the downregulation of IFN-I receptor (IFNAR1) is associated with a poor clinical outcome and tumor progression in melanoma 7 , breast and colorectal cancers 8,9 .

The precise role of pDCs within the TME remains unclear. While pDC infiltration within tumors was correlated with positive prognosis in colorectal and pancreatic cancers, pDCs were associated with a negative prognosis in ovarian cancer. In breast cancer, they were associated with a positive or negative prognosis 10 . In this context, we and others have demonstrated that pDCs are dysregulated in the TME, displaying a particularly poor capacity to secrete IFN-α 11-13 . This was