Type III interferon primes pDCs for TLR7 activation and antagonizes immune suppression mediated by TGF-β and PGE2

Abstract

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.