Separate molecular pathways mediate anti-tumor versus tumor-promoting aspects of Poly-I:C signaling in cancer microenvironments

Abstract Background We have previously shown that Poly-I:C, a frequently used adjuvant, induces both the CTL-attracting chemokines and Treg attractants. Here we evaluated the molecular pathways, which lead to the induction of chemokines by poly-I:C in TME and different types of tumor-associated cells, in order to develop improved adjuvants which selectively attract the desirable effector cells rather than suppressive cells. Methods Isolated cells or human cancer biopsies were cultured for 0.5–48 hours in the absence or presence of one of two synthetic TLR3 ligands Poly-I:C (non-selective activator of TLR3 and helicases) rintatolimod (selective TLR3 ligand), in the absence or presence of a COX-1/2 inhibitor, NF-kB- and TNFa inhibitors. mRNA assays, confocal microscopy, ELISA, chemotaxis assays and molecular biology assays were used to analyze the chemokine production and tumor-associated suppressive factors. Results We observed that poly-I:C induced activation of NF-kB- and COX-2 pathways leading to induction of COX2-dependent suppressive factors and Treg- and MDSC-attracting chemokines. These undesirable effects were blocked with inhibitors of both NF-kB- or COX-2 pathways. In contrast rintatolimod selectively induced the desirable chemokines, which were associated with lack of direct activation of NF-kB- or COX-2 pathways, and strongly suppressed attraction of Tregs and MDSCs, with elevated CTL attraction in ex vivo migration assays. Conclusion Our data implicates an important new role of helicases by the induction of tumor-promoting factors by dsRNA and points out to new targets to enhance the immunogenic and antitumor activities of adjuvants.