The oncolytic virusdl922-947 reduces IL-8/CXCL8 and MCP-1/CCL2 expression and impairs angiogenesis and macrophage infiltration in anaplastic thyroid carcinoma

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.

The immune network in thyroid cancer

“…53 Targeting these mediators could be exploited to block TC growth, since this strategy has been already developed for other tumors. 116 Moreover, boosting anticancer immune responses by blocking immunosuppressive molecules (TGF-b, IL-10, CTLA-4, PD-1 and PD-L1) expressed either by cancer cells or by tumor-infiltrating immune cells 117 and cytolytic viruses approaches 51 appear promising therapeutic strategies in different tumors, including TC.…”

“…50 We have recently found that the oncolytic adenovirus dl922-947 reduced CXCL8/IL-8 and CCL2 production by ATC cell lines. 51 Interestingly, dl922-947 treatment impaired ATCinduced angiogenesis and favored the switch of tumor macrophages toward an M1 phenotype. These results indicate that dl922-947 treatment, along with its role in inducing TC cell death, impacts on ATC immune microenvironment.…”

Aberrant Thyroid-Stimulating Hormone Receptor Signaling Increases VEGF-A and CXCL8 Secretion of Thyroid Cancer Cells, Contributing to Angiogenesis and Tumor Growth

“…Previously, several studies have demonstrated that TSH or tumor necrosis factor-a stimulated CXCL8 production in normal thyrocytes, playing a role in the immune process in thyroiditis (21,40). In the thyroid cancer microenvironment, CXCL8, originating from mast cells or macrophages (41,42), has been established as an angiogenic cytokine that modulates tumor vasculature (41,43). Herein, we first demonstrated that TSH upregulated CXCL8 production in thyroid cancer cells.…”

Underestimated Infection - On the Question of the Human Adenovirus Pathogenicity Factors

“…В свою очередь альвеолярные макрофаги, модулируя экспрессию ИЛ-1β, ИЛ-6, ИЛ-8, ФНОα и других провоспалительных цитокинов, играют ключевую роль в инициации воспалительного ответа, ассоциированного с ОРДС. В то же время штамм HAdv с делетированной последовательностью E1B 19K, снижал продукцию ИЛ-8 и CCL2 (фактор хемотаксиса моноцитов) в клетках анапластической тиреоидной карциномы человека как на уровне мРНК, так и на уровне белка [42].…”