The purpose of this study was to investigate the therapeutic potential of interferon-β (IFN-β) against tumors that resist its antiproliferative effects. Mouse fibrosarcoma cells (UV-2237m-P) and their counterparts, transfected with either IFN-β cDNA (UV-2237m-IFN-β) or its control vector (UV-2237m-neo), were used in the study. UV-2237m-IFN-β cells, still expressing functional IFN receptors, were resistant to the antiproliferative effects of IFN-β. UV-2237m-P and UV-2237m-neo cells produced progressive tumors in both nude and IFN receptor-null nude (IFNAR−/−nude) mice. In contrast, growth of UV-2237m-IFN-β cells was significantly delayed in nude mice. UV-2237m-IFN-β tumors from nude mice contained fewer microvessels, fewer proliferating cells, and more apoptotic cells than did UV-2237m-P and UV-2237m-neo tumors. They expressed high levels of inducible nitric oxide synthase (iNOS) and were densely infiltrated by macrophages. Incubation with macrophages from nude mice, but not those from IFNAR−/− nude mice or iNOS-null/nude mice, led to more significant killing of UV-2237m-IFN-β cells than that of control cells, which was blocked by iNOS inhibitor N-methylarginine. Similarly, more UV-2237m-IFN-β cells were killed when they were incubated with spleen lymphocytes from nude mice. These data indicate that IFN-β can inhibit growth of IFN-β-resistant tumors by T cell-independent host-mediated mechanisms, including the role of macrophages, natural killer (NK) cells, and iNOS activity.
