These receptors are expressed mainly on APCs. Both compounds strongly enhance antigen-specific CD8+ Daporinad ic50 T-cell responses, promoting antigen cross-presentation by dendritic cells (DCs), and directly acting on effector CD8+ T cells and natural killer cells to augment

IFN-γ release [4-7]. A direct effect of synthetic dsRNA on cancer cells has also been demonstrated, since they are capable of inducing the production of type I IFNs, which in turn promotes the apoptosis of cancer cells through an autocrine signaling loop [8-11]. Both poly I:C and poly A:U are strong inducers of type I IFNs. Type I IFNs can be produced by almost any cell type in the body in response to stimulation of TLR3, RLRs, and many other receptors [12]. Exogenously administered type I IFNs were used with some success (and a substantial number of toxic side effects) in anticancer therapy [13]. In contrast,

the role of endogenous type I IFNs in cancer therapy has only recently begun to be elucidated [14-17]. We have recently shown that when murine tumorigenic cancer cells are stimulated in vitro with a TLR4 ligand such as lipopolysaccharide (LPS) prior to their inoculation into TLR4-deficient mice, they yield smaller tumors than those elicited by nonstimulated cells. The Palbociclib purchase apoptosis/proliferation balance of LPS-stimulated cancer cells was neither modified, nor was this effect observed in athymic nude mice [18]. Interestingly, the inhibition of tumor growth observed was associated to the presence of DCs with a more mature phenotype as well as increased frequencies

of CD11c+ IL-12+ and CD3+ IFN-γ+ tumor infiltrating cells. Moreover, IFN-β secreted by TLR4-activated tumor cells was involved in improving DC maturation and IL-12 production in vitro. Mechanistic investigations revealed that IFN-β was the critical factor produced by TLR4-activated tumor cells, since tumor growth inhibition was abrogated in IFNAR1-deficient mice lacking a functional type I IFN receptor for binding IFNs [19]. These findings LY294002 prompted us to investigate if other TLR ligands, known to be stronger inducers of type I IFNs, could also stimulate tumor cells to produce IFN-β and positively contribute to the antitumoral immune response. We focused specifically on TLR3 ligands, currently proposed as effective adjuvants in different therapeutic settings [20, 21]. In the present work, we show that dsRNA-activated murine B16 melanoma cells also produce high levels of IFN-β. Moreover, B16 cells activated in vitro with poly A:U and then inoculated into TLR3-deficient mice elicited smaller tumors. Again, this tumor growth inhibition was abrogated in IFNAR1-deficient mice. Furthermore, poly I:C-stimulated human cancer cell lines can also be a source of IFN-β, at levels that are capable of improving the maturation state of human monocyte derived DCs (MoDCs) and reversing the suppressive effect of tumor cell derived factors on MoDC maturation [22, 23].