A Novel Immune-Based Cancer Therapy Using Gene-Silenced Dendritic Cells (48.8)

Abstract

Abstract Hyporesponsiveness is a major hallmark in dendritic cells (DC)-mediated anticancer immunotherapy. Indoleamine 2, 3-dioxygenase (IDO), an immunosuppressive molecule expressed by DC, is a critical factor mediating hyporesponsiveness to cancer immune therapy. We hypothesized that silencing of IDO in DC using siRNA would enhance anticancer therapy. In this study, DC were cultured in vitro, exposed to melanoma B16 lysate, silenced with IDO siRNA, and injected into C57/BL6 mice. Mice were then challenged with B16 tumor cells. The anticancer effects of IDO-silenced DC therapy, compared with non-silenced, conventional control DC vaccine, were evidenced by postponed melanoma tumor onset time, anddecreased tumor size. In addition, after immunization with IDO-silenced DC, the number of CD8+ T cells was significantly increased while CD4+ and CD8+ T cell apoptosis in draining lymph nodes was remarkably reduced. Furthermore, immunization with IDO-silenced DC enhanced tumor antigen-specific T cell proliferation and CTL activity, and decreased numbers of CD4+CD25+FoxP3+ regulatory T cells (Treg). In conclusion, this study is the first to demonstrate a novel anti-tumor vaccine by silencing an immunosuppressive gene (IDO) in DC, which enhanced anti-tumor immunity, reduced T cell apoptosis and Treg cell formation, and prevented tumor growth. IDO-silenced DC have clinical potential as an immune-based therapy.