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

GERARDO GATTI, NICOLÁS GONZALO NUÑEZ, DAVID ANDRÉS NOCERA, LIEN DEJAGER, CLAUDE LIBERT, CONSTANCIO GIRAUDO, MARIANA MACCIONI

EUROPEAN JOURNAL OF IMMUNOLOGY

WILEY-V C H VERLAG GMBH

Lugar: Weinheim; Año: 2013 vol. 43 p. 1849 - 1861

0014-2980

Viral double-stranded RNA (dsRNA) mimetics have been explored in cancer immunotherapy to promote antitumoral immune response. Polyinosine-polycytidylic acid (poly I:C) and Polyadenylic?polyuridylic acid (poly A:U) are synthetic analogs of viral dsRNA and strong inducers of type I Interferon (IFN). We describe here a novel effect of dsRNA analogs on cancer cells: besides their potential to induce cancer cell apoptosis through an IFN-β autocrine loop, dsRNA-elicited IFN- production improves dendritic cell functionality. Human A549 lung and DU145 prostate carcinoma cells significantly responded to poly I:C stimulation, producing IFN- at levels that were capable of activating STAT1 and enhancing CXCL10, CD40 and CD86 expression on human monocyte-derived dendritic cells (MoDCs). IFN-produced bypoly I:C-activated human cancer cells increased the capacity of MoDCs to stimulate IFN-γ production in an allogeneic stimulatory culture in vitro. When melanoma murine B16 cells were stimulated in vitro with poly A:U and then inoculated into TLR3-/- mice, smaller tumors were elicited. This tumor growth inhibition was abrogated in IFNAR1-/- 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 response.