title: Modulation of antitumour immune responses by intratumoural Stat1 expression.
abstract: Signal transducer and activator of transcription 1 (Stat1) mediates anti-viral responses and cytokine-driven anti-proliferative, apoptotic and immunomodulatory activities. As de-regulated Stat1 function can affect tumour progression we sought to elucidate the effects of tumour cell-intrinsic Stat1 expression on immunosurveillance. Knockout of Stat1 enhanced the development of sarcomas induced by the chemical carcinogen 3-methylcholanthrene (MCA). Growth of transplanted MCA-induced Stat1⁻/⁻ sarcomas was suppressed in wild-type mice compared to growth in Stat1⁻/⁻ and immunocompromised recipients. Co-depletion of NK and CD8⁺ T cells from wild-type mice facilitated Stat1-deficient tumour growth whereas depletion of CD4⁺ T cells and CD8⁺ T cells did not. In vitro and in vivo analysis of the tumours implicated a role for NK cell-mediated, perforin-dependent killing of Stat1-deficient tumours. Interestingly, restoration of Stat1 expression in Stat1⁻/⁻ tumours resulted in diminished involvement of NK cells and increased contribution of CD8⁺ T cells in anti-tumour responses. Therefore, Stat1 expression within tumour cells modulated anti-tumour immune responses by altering the dominant immune effector cell involvement from NK cells to CD8⁺ T cells in the absence or presence of Stat1 respectively.
authors: 1] Cancer Therapeutics Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia [2] Deptartment of Pathology, University of Melbourne, Parkville, Victoria, Australia.
authors: Nicole L
authors: NL
authors: Messina
authors: Kellie M
authors: KM
authors: Banks
authors: Eva
authors: E
authors: Vidacs
authors: Ben P
authors: BP
authors: Martin
authors: Fennella
authors: F
authors: Long
authors: Ailsa J
authors: AJ
authors: Christiansen
authors: Mark J
authors: MJ
authors: Smyth
authors: Christopher J P
authors: CJ
authors: Clarke
authors: Ricky W
authors: RW
authors: Johnstone
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D048708:Cell Growth Processes / Q000235:genetics; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology*; D008212:Lymphocyte Depletion; D008748:Methylcholanthrene / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015166:Monitoring, Immunologic; D009368:Neoplasm Transplantation; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D012513:Sarcoma, Experimental / Q000139:chemically induced / Q000276:immunology*
chemical_list: D050794:STAT1 Transcription Factor; D008748:Methylcholanthrene