Abstract
Abstract Previously, we reported in C57Bl/6 (B6) and IRF3KO mice that Interferon Regulatory Factor (IRF-3) contributes to control of B16 melanoma tumor growth. Moreover we found a link between IRF-3 and expression of IFN-γ during in vitro T cell responses of B6 and IRF3KO mice. To investigate IRF3 and IFN-γ expression at growing tumors, we injected B6 and IRF3KO mice sq with B16-F10 tumor cells that constitutively express luciferase. Tumor growth was similar between B6 and IRF3KO mice at day 2 and 6, but was significantly greater at day 9 in IRF3KO mice compared with B6 mice. Using transcription factor assays of spleen extracts, IRF3 and IRF7 activation peaked at day 6 in B6 tumor-bearing mice but failed to occur in IRF3KO mice post injection. Likewise, significant induction of IFN-γ occurred in spleens and tumors in tumor-bearing B6 mice but failed to occur in tumor-bearing IRF3KO mice from day 6–9 post injection. Previous reports from other labs showed that the anti-tumor properties of IFN-γ are the result of G1/G0 cell cycle arrest. Using B16 cells or B16 cells deficient in IFN-γ receptor (B16-IRFGRKO), we found that IFN-γ decreases B16 tumor cell growth and synergizes with the TLR3/IRF3 agonists, poly I:C, in decreasing B16 cell growth. Concomitantly, IFN-γ induced interferon stimulated gene-54 (ISG54), which is IRF3 dependent and promotes apoptosis in cells. Moreover, we treated B16-SEAP and B16-SEAPIFNGRKO cells, which express secreted alkaline phosphatase (SEAP) under the control of an ISG54/ISRE promoter. We found that IFN-γ induces ISG54 promoter activity and poly I:C synergizes with IFN-γ to induce ISG54 in B16 cells. Thus an IFN-γ/IRF3/ISG54 nexus can significantly contribute to tumor cell control during anti-tumor immune responses.
Published Version
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