The oncolytic virus dl922-947 reduces IL-8/CXCL8 and MCP-1/CCL2 expression and impairs angiogenesis and macrophage infiltration in anaplastic thyroid carcinoma.

// 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 “G. Salvatore”, 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’ 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-κB 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-γ. 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.