Anticancer therapy by hybrids of dendritic cells and interferon-α-overexpressing cells

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Dendritic cell (DC)-based immunotherapy has been used clinically against cancer although most attempts showed insufficient responses. Fusion technique for DCs and tumor cells has been developed and widely used in experimental models as well as clinical trials. To overcome an immunosuppressed state in patients with tumors, tumor-based vaccination in combination with cytokine gene therapy has also been used in treatment of these tumors. We previously showed the efficacy of IFN-α-overexpressing tumor in a murine poorly immunogenic colorectal cancer model. Therefore, we thought that immunotherapy using hybrids of DCs and IFN-α-overexpressing tumor cells might have more antitumor effects compared with therapy with hybrids of DCs and wild-type cells. In this study, we evaluated antitumor effects of therapy with hybrids of DCs and IFN-α gene transduced colorectal cancer cells in a murine model. We established an IFN-α-overexpressing MC38 colorectal cancer cell line (MC38-IFNα, producing 157.0 … More +-4.2 ng of IFN-α/10^6cells/48h) using a retroviral vector. We made hybrids of DCs and MC38-IFNα cells with polyethyleneglycol. To evaluate the preventive effects, the hybrids were injected in immunocompetent mice 7 days before injection of wild-type MC38 (MC38-WT). As a therapy against established tumors, hybrids were inoculated contralaterally 7 days after MC38-WT cells had been injected. Hybrids were detected 17-25% of the fused DCs and MC38-IFNα cells, and these cells produced a large amount of IFN-α. Preinjection of hybrids prevented implantation of wild-type tumors effectively in all mice. In the therapeutic model against established tumors, hybrids of DCs and MC38-IFNα cells suppressed growth of the tumors more effectively than hybrids of DCs and MC38-WT cells. Immunohistochemical analysis showed marked infiltration of CD8^+ cells in the established tumors of mice treated with hybrids of DCs and MC38-IFNα cells. Immunotherapy using hybrids of DCs and IFN-α-transduced tumor cells induces cellular antitumor immune response effectively, and should be considered in clinical trials. Less