Adenovirally delivered IFN-beta exerts antitumor effects through transient T-lymphocyte depletion and Ag-specific T-cell proliferation

Abstract

Type I interferons (IFNs), including IFN-beta, are known to enhance antigen (Ag) presentation and to promote the expansion, survival and effector function of CD8(+) cytotoxic lymphocytes (CTL) during viral infections. Furthermore, IFN-beta is a potent candidate for antitumor drugs; however, recombinant IFN-beta is too unstable for use in tumor therapy in vivo. In this study, we therefore examined the efficacy and mechanism of exogenous IFN-beta as a biomolecule for tumor therapy, using adenovirus encoding IFN-beta (Ad-IFN beta) as a therapeutic agent in a mouse model. Ag104L(d) and 4T1 tumor cells exposed to Ad-IFN beta showed growth retardation and cell death in vitro, and tumor growth as well as tumor metastasis was inhibited in vivo. The Ad-IFN beta-mediated antitumor effect was dependent on CD8(+) T cells in vivo, rather than on a direct cytotoxic effect of Ad-IFN beta. Transient T lymphocyte depletion was observed in tumor tissue after intratumoral injection with Ad-IFN beta. Despite the T lymphocyte depletion, the proliferation of Ag-specific CD8(+) T cells was increased in Ad-IFN beta-treated mice compared to control virus-treated mice. These results suggest that IFN-beta might contribute to the inhibition of tumor growth by depleting Ag-nonspecific T lymphocytes and enhancing proliferation of Ag-specific CD8(+) T cells.