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 dl922-947 induces ATC cell death in vitro and tumor regression in vivo. However, the impact of dl922-947 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 dl922-947 virotherapy has such effect on ATC cells, thereby modulating ATC microenvironment. dl922-947 decreased IL-8/CXCL8 and MCP-1/CCL2 production by the ATC cell lines 8505-c and BHT101-5. These results correlated with dl922-947-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. dl922-947-mediated reduction of IL-8 impaired ATC cell motility in vitro and ATC-induced angiogenesis in vitro and in vivo. We also show that dl922-947-mediated reduction of the monocyte-attracting chemokine CCL2 decreased monocyte chemotaxis in vitro and tumor macrophage density in vivo. Interestingly, dl922-947 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 dl922-947 treatment re-shape the pro-tumorigenic ATC microenvironment by modulating cancer-cell intrinsic factors and the immune response. An in-depth knowledge of dl922-947-mediated effects on ATC microenvironment may help to refine ATC virotherapy in the context of cancer immunotherapy.
Highlights
Tumorigenesis is a multistep process that involves cancer cell-intrinsic alterations and complex interactions with tumor stroma and infiltrating immune cells [1, 2]
We demonstrate that dl922-947 treatment affects tumor angiogenesis and macrophage density, two hallmarks of the pro-tumorigenic Anaplastic thyroid carcinoma (ATC) microenvironment
The production of IL-8 by ATC cells is involved in several aspects of tumorigenesis, namely induction of angiogenesis, epithelial-tomesenchymal transition and stemness [35, 37]
Summary
Tumorigenesis is a multistep process that involves cancer cell-intrinsic alterations and complex interactions with tumor stroma and infiltrating immune cells [1, 2]. In several experimental neoplastic models, including ATC, dl922947 treatment, alone or in combination with molecularly-targeted drugs or ionizing radiations, can induce cancer cell death and tumor regression [23,24,25,26,27,28,29,30]. These studies were aimed to demonstrate synergistic effects of the combined treatments, we observed an anti-angiogenic effect of the virus [29]. We provide evidence that dl922-947-induced reduction of IL-8 and CCL2 production correlates with impaired tumor angiogenesis and decreased macrophage density in vitro and in vivo
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