The role of STAT2 in mediating the antigrowth effects of type I interferon (IFN) is well-documented in vitro. Yet evidence of IFN-activated STAT2 as having tumor suppressor function in vivo and participation in antitumor immunity is lacking. Here we show in a syngeneic tumor transplantation model that STAT2 reduces tumor growth. Stat2−/− mice formed larger tumors compared to wild type (WT) mice. IFN-β treatment of Stat2−/− mice did not cause tumor regression. Gene expression analysis revealed a small subset of immunomodulatory genes to be downregulated in tumors established in Stat2−/− mice. Additionally, we found tumor antigen cross-presentation by Stat2−/− dendritic cells to T cells to be impaired. Adoptive transfer of tumor antigen specific CD8+ T cells primed by Stat2−/− dendritic cells into tumor-bearing Stat2−/− mice did not induce tumor regression with IFN-β intervention. We observed that an increase in the number of CD4+ and CD8+ T cells in the draining lymph nodes of IFN-β-treated tumor-bearing WT mice was absent in IFN-β treated Stat2−/− mice. Thus our study provides evidence for further evaluation of STAT2 function in cancer patients receiving type I IFN based immunotherapy.What's new?
Type I interferons (IFN-I) are used to treat cancer due to their critical immune modulatory and anti-proliferative properties. Here, the authors provide in vivo evidence that the transcription factor STAT2 plays a key role in the antitumor activity of IFN-I by controlling tumor growth and promoting tumor antigen cross-presentation. Using microarray analysis, they identified a small subset of STAT2-dependent genes that actively direct antitumor immunity. These findings identify STAT2 as a critical player in IFN-I immunotherapy and a potential target for future drug development.