IFN-III primes pDCs for TLR7 activation and antagonizes TGF-β mediated-immune suppression in tumors

Abstract Conventional dendritic cell (cDC1, cDC2) and plasmacytoid dendritic cell (pDCs) subsets have specialized functions that can be modulated by the tumor microenvironment (TME). These cells produce different interferons that are central to antitumor immune responses. While the role of Type I Interferons (IFN-I) in tumor immunity is well characterized, the role of Type III interferons (IFN-III) produced by cDC1 in the TME which is associated with good outcome remains completely unknown. Here, we demonstrate that IFN-III orchestrates pDCs survival, activation and TLR7 expression in the blood and in tumors, enhancing their capacity to respond to TLR7-ligand. Importantly, IFN-III prevents the inhibition of pDCs induced by the TME or by TGF-β, a dominant TME inhibitory cue, and restores their production of IFN-α. Because of the essential role of TGF-β in immune regulation, this mechanism is expected to impact other pathological situations.