Membrane-bound form of monocyte chemoattractant protein-1 enhances antitumor effects of suicide gene therapy in a model of hepatocellular carcinoma

作者：Marukawa Y; Nakamoto Y; Kakinoki K; Tsuchiyama T; Iida N; Kagaya T; Sakai Y; Naito M; Mukaida N; Kaneko S^*

来源：Cancer Gene Therapy, 2012, 19(5): 312-319.

DOI：10.1038/cgt.2012.3

• herpes simplex virus thymidine kinase
• hepatocellular carcinoma
• membrane-bound form
• monocyte chemoattractant protein-1
• monocyte/macrophages

Suicide gene therapy using the herpes simplex virus thymidine kinase/ganciclovir (HSV-tk/GCV) system combined with monocyte chemoattractant protein-1 (MCP-1) provides significant antitumor efficacy. The current study was designed to evaluate the antitumor immunity of a newly developed membrane-bound form of MCP-1 (mMCP-1) in an immunocompetent mouse model of hepatocellular carcinoma (HCC). A recombinant adenovirus vector (rAd) harboring the human MCP-1 gene and the membrane-spanning domain of the CX3CL1 gene was used. Large amounts of MCP-1 protein were expressed and accumulated on the tumor cell surface. The growth of subcutaneous tumors was markedly suppressed when tumors were treated with mMCP-1, as compared with soluble MCP-1, in combination with the HSV-tk/GCV system (P%26lt;0.01). The numbers of Mac-1-, CD4- and CD8a-positive cells were significantly higher in tumor tissues (P%26lt;0.05), and tumor necrosis factor (TNF) mRNA expression levels with mMCP-1 were almost five-fold higher than those with soluble MCP-1. These results indicate that the delivery of the mMCP-1 gene greatly enhanced antitumor effects following the apoptotic stimuli by promoting the recruitment and activation of macrophages and T lymphocytes, suggesting a novel strategy of immune-based gene therapy in the treatment of patients with HCC.

• 出版日期2012-5