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 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.
Lesinski
Gregory B
GB
Department of Human Cancer Genetics, The Ohio State University, Columbus, Ohio 43210, USA.
Anghelina
Mirela
M
Zimmerer
Jason
J
Bakalakos
Timothy
T
Badgwell
Brian
B
Parihar
Robin
R
Hu
Yan
Y
Becknell
Brian
B
Abood
Gerard
G
Chaudhury
Abhik Ray
AR
Magro
Cynthia
C
Durbin
Joan
J
Carson
William E
WE
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002455:Cell Division; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D018014:Gene Transfer Techniques; D015151:Immunoblotting; D007150:Immunohistochemistry; D016898:Interferon-alpha / Q000494:pharmacology*; D007694:Killer Cells, Natural; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D008822:Mice, Transgenic; D012190:Retroviridae / Q000235:genetics; D050794:STAT1 Transcription Factor; D015398:Signal Transduction; D013154:Spleen / Q000166:cytology; D013997:Time Factors; D015534:Trans-Activators / Q000235:genetics* / Q000502:physiology*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D016898:Interferon-alpha; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D015534:Trans-Activators