Direct effect of dsRNA mimetics on cancer cells induces endogenous IFN production capable of improving dendritic cells function

GERARDO GATTI; NICOLÁS G NÚÑEZ; DAVID ANDRÉS NOCERA; LIEN DEJADER; CLAUDE LIBERT; CONSTANCIO GIRAUDO; MARIANA MACCIONI

EUROPEAN JOURNAL OF IMMUNOLOGY

WILEY-V C H VERLAG GMBH

Lugar: Weinheim; Año: 2013 vol. 43 p. 1 - 13

0014-2980

The use of viral double-stranded RNA (dsRNA) mimetics in cancer immunotherapy has been explored for several decades with the idea of enhancing innate and adaptive immune responses and altering the tumor microenvironment. Polyinosine-polycytidylic acid (poly I:C) and Polyadenylic?polyuridylic acid (poly A:U) are synthetic analogs of viral dsRNA, which are strong inducers of a type I Interferon (IFN) response. In this work, we describe a novel effect of dsRNA analogs on cancer cells: besides their potential of inducing cancer cell apoptosis through an IFNβ autocrine loop, dsRNA-elicited IFN production is enough to improve dendritic cell functionality, which could in turn, improve the antitumoral immune response. Human A549 lung and DU145 prostate carcinoma cells significantly respond to poly I:C stimulation, producing IFN, at levels that are capable of activating STAT1 and enhancing CD40 and CD86 expression on human monocyte-derived dendritic cells (Mo-DC). Also, IFNproduced bypoly I:C-activated human cancer cells increase the capacity of Mo-DCs of stimulating IFN-γ production in an allogeneic stimulatory culture in vitro. Moreover, when melanoma murine B16 cells were stimulated in vitro with poly A:U and then inoculated into TLR3 deficient mice, they elicited smaller tumors. This tumor growth inhibition was abrogated in IFNAR1-deficient mice. Thus, dsRNA compounds are effective adjuvants not only because they activate DCs and promote strong adaptive immunity, but also because they can directly act on cancer cells to induce endogenous IFN production and contribute to the antitumoral immune response.