The antitumor effects of IFN- alpha are abrogated in a STAT1-deficient mouse

IFN- alpha activates the signal transducer and activator of transcription (STAT) family of proteins; however, it is unknown whether IFN- alpha exerts its antitumor actions primarily through a direct effect on malignant cells or by stimulating the immune system. To investigate the contribution of STAT1 signaling within the tumor, we generated a STATl-deficient melanoma cell line, AGS-1. We reconstituted STAT1 into AGS-1 cells by retroviral gene transfer. The resulting cell line (AGS-1 super(STAT1)) showed normal regulation of IFN- alpha -stimulated genes (e.g., H2k, ISG-54) as compared with AGS-1 cells infected with the empty vector (AGS-1 super(MSCV)). However, mice challenged with the AGS-1, AGS-1 super(STAT1), and AGS-1 super(MSCV) cell lines exhibited nearly identical survival in response to IFN- alpha treatment, indicating that restored STAT1 signaling within the tumor did not augment the antitumor activity of IFN- alpha . In contrast, STAT1 super(-/-) mice could not utilize exogenous IFN- alpha to inhibit the growth of STAT1 super(+/+) melanoma cells in either an intraperitoneal tumor model or in the adjuvant setting. The survival of tumor-bearing STATI super(-/-) mice was identical regardless of treatment (IFN- alpha or PBS). Additional cell depletion studies demonstrated that NK cells mediated the antitumor effects of IFN- alpha . Thus, STAT1-mediated gene regulation within immune effectors was necessary for mediating the antitumor effects of IFN- alpha in this experimental system.