HOST TYPE I IFN SIGNALS ARE REQUIRED FOR THE ANTITUMOR IMMUNE RESPONSE ELICITED BY THE THERAPEUTICALLY ADMINISTERED TLR3 LIGAND POLY AU

NOCERA, DAVID; NICOLAS NUÑEZ; GATTI, GERARDO; EMILIANO ROSELLI; PAULA ARAYA; ESTEFANÍA ZACCA; GABRIEL MORÓN; MARIANA MACCIONI

Los Cocos

Congreso; LXI Reunión Anual de la Sociedad Argentina de Inmunología; 2013

Sociedad Argentina de Inmunología

Introduction: 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. Polyadenylic?polyuridylic acid (pAU) is a synthetic analog of viral dsRNA recognized mainly by Toll like receptor 3 (TLR3) capable of triggering type I IFN production. The main goal of this work was to analyze the effect of intratumorally (i.t.) administered pAU on the specific immune response against tumor antigens in mice lacking the IFNAR1 subunit of the type I IFN receptor (ifnar1-/-). Material and Methods: B16 murine melanoma cells expressing Ovalbumin (OVA) were inoculated s.c. in wild-type and ifnar1-/- mice. When tumors reached a measurable size (~day 12 p.i), a group of mice from each strain was i.t. treated with 50 μg of pAU (n=10, 4 doses every two days). Results: pAU-treated wild-type mice showed a significantly reduced tumor growth as well as a longer survival compared to controls (p<0.001, n=10). However, results obtained using genetically modified mice indicated that recognition of type I IFN is necessary for this effect. When tumor infiltrating leucocytes were analyzed by flow cytometry or immunofluorescence on tumor sections, a lower percentage of CD45+ cells were found in ifnar1-/- mice (p<0.01, n=5). To study the specific immune response against OVA, CD8+ or CD4+ T cells from transgenic OTI and OTII mice respectively were adoptively transferred into PBS and pAU-treated tumor bearing mice of both strains. A higher frequency of tumor infiltrating OVA-specific CD8+IFNγ+CD107+ as well as CD4+IFNγ+ cells were found in pAU treated wild-type mice (p<0.001, n=5). Discussion: Our findings extend the knowledge on dsRNA mimetics as effective adjuvants in therapeutic settings, providing in vivo evidence of their capacity of generating antitumoral response and underlying the importance of host type I IFN in the mentioned effect.