The oncolytic virus<i>dl</i>922-947 reduces IL-8/CXCL8 and MCP-1/CCL2 expression and impairs angiogenesis and macrophage infiltration in anaplastic thyroid carcinoma

Abstract

// Carmela Passaro 1,* , Francesco Borriello 1,2,* , Viviana Vastolo 1 , Sarah Di Somma 1 , Eloise Scamardella 1 , Vincenzo Gigantino 3 , Renato Franco 4 , Gianni Marone 1,2,3 and Giuseppe Portella 1 1 Department of Translational Medical Sciences, University of Naples Federico II, Naples, Italy 2 Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, Naples, Italy 3 CNR Institute of Experimental Endocrinology and Oncology &ldquo;G. Salvatore&rdquo;, Naples, Italy 4 Experimental Oncology, IRCCS Fondazione Pascale, Naples, Italy * These authors have contributed equally to this work Correspondence to: Giuseppe Portella, email: // Keywords : virotherapy, tumor vasculature, innate immunity, tumor-associated macrophages, chemokine Received : July 08, 2015 Accepted : November 15, 2015 Published : November 29, 2015 Abstract Anaplastic thyroid carcinoma (ATC) is one of the most aggressive human solid tumor and current treatments are ineffective in increasing patients&rsquo; survival. Thus, the development of new therapeutic approaches for ATC is needed. We have previously shown that the oncolytic adenovirus dl 922-947 induces ATC cell death in vitro and tumor regression in vivo . However, the impact of dl 922-947 on the pro-tumorigenic ATC microenvironment is still unknown. Since viruses are able to regulate cytokine and chemokine production from infected cells, we sought to investigate whether dl 922-947 virotherapy has such effect on ATC cells, thereby modulating ATC microenvironment. dl 922-947 decreased IL-8/CXCL8 and MCP-1/CCL2 production by the ATC cell lines 8505-c and BHT101-5. These results correlated with dl 922-947-mediated reduction of NF-&kappa;B p65 binding to IL8 promoter in 8505-c and BHT101-5 cells and CCL2 promoter in 8505-c cells. IL-8 stimulates cancer cell proliferation, survival and invasion, and also angiogenesis. dl 922-947-mediated reduction of IL-8 impaired ATC cell motility in vitro and ATC-induced angiogenesis in vitro and in vivo . We also show that dl 922-947-mediated reduction of the monocyte-attracting chemokine CCL2 decreased monocyte chemotaxis in vitro and tumor macrophage density in vivo . Interestingly, dl 922-947 treatment induced the switch of tumor macrophages toward a pro-inflammatory M1 phenotype, likely by increasing the expression of the pro-inflammatory cytokine interferon-&gamma;. Altogether, we demonstrate that dl 922-947 treatment re-shape the pro-tumorigenic ATC microenvironment by modulating cancer-cell intrinsic factors and the immune response. An in-depth knowledge of dl 922-947-mediated effects on ATC microenvironment may help to refine ATC virotherapy in the context of cancer immunotherapy.