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

J Clin Invest. 2003 Jul;112(2):170-80. doi: 10.1172/JCI16603.


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 STAT1-deficient melanoma cell line, AGS-1. We reconstituted STAT1 into AGS-1 cells by retroviral gene transfer. The resulting cell line (AGS-1STAT1) 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-1MSCV). However, mice challenged with the AGS-1, AGS-1STAT1, and AGS-1MSCV 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-/- mice could not utilize exogenous IFN-alpha to inhibit the growth of STAT1+/+ melanoma cells in either an intraperitoneal tumor model or in the adjuvant setting. The survival of tumor-bearing STAT1-/- 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Cell Division
  • Cell Line
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / physiology*
  • Dose-Response Relationship, Drug
  • Flow Cytometry
  • Gene Expression Regulation
  • Gene Transfer Techniques
  • Immunoblotting
  • Immunohistochemistry
  • Interferon-alpha / pharmacology*
  • Killer Cells, Natural
  • Mice
  • Mice, Inbred C57BL
  • Mice, SCID
  • Mice, Transgenic
  • Retroviridae / genetics
  • STAT1 Transcription Factor
  • Signal Transduction
  • Spleen / cytology
  • Time Factors
  • Trans-Activators / genetics*
  • Trans-Activators / physiology*
  • Tumor Cells, Cultured


  • Antineoplastic Agents
  • DNA-Binding Proteins
  • Interferon-alpha
  • STAT1 Transcription Factor
  • Stat1 protein, mouse
  • Trans-Activators