CONICET | Buscador de Institutos y Recursos Humanos

Polyadenylic?polyuridylic acid (pAU) is a synthetic analog of viral dsRNA, recognized mainly by TLR3 and capable of triggering type I IFN production. Whereas exogenously administered type I IFN was used with some success in anti-cancer therapy, the role of endogenous type I IFNs in cancer has only recently begun to be elucidated. Intratumor administration of pAU in tumor- bearing mice reduces tumor growth, increases mice survival and enhances the specific immune response against tumor antigens. Recognition of type I IFN by host cells is crucial for this effect. In this work, we extend our data regarding the capacity of pAU of eliciting endogenous type I IFN production in therapeutic settings. To visualize the endogenous production of IFN-β, B16 tumors were generated in IFNβ reporter mice which have the luciferase reporter gene under the control of the IFNβ promoter (IFN β + / Δβ Luc). IFNβ induction in vivo was visualized after i.p injection of D-luciferin and monitoring luciferase induction in an IVIS 200 imaging system. Alternatively, tumors were induced in tissue specific reporter mice, which express luciferase in LysM+ or CD11c+cells. When tumors reached a measurable size a group of tumor-bearing mice was intratumorally treated with 50 µg of pAU (n=10, 4 doses every two days). Kinetics studies revealed that IFNβ was effectively induced after 6hs of pAU-treatmet and that this production decreases after consecutive doses. Furthermore, LysM+ and CD11c+ cells were mainly responsible of host IFNβ induction within tumor (93.1 and 45.8 relative luciferase units RLU -% of global- respectively). B16 tumors were also generated in IRF3 -/-, IRF5-/-, IRF7-/- , UNC93b1-/- reporter IFNβ +/ Δβ Luc mice. Our results indicate that IRF3 and UNC93b1 proteins are directly involved in the induction of IFNβ in our pre-clinical model. These data shed light about the mechanisms of IFNβ induction in preclinical therapeutic models of pAU administration.