Modulation of antitumour immune responses by intratumoural Stat1 expression

• Published in: Immunology and cell biology Vol. 91; no. 9; pp. 556 - 567
• Main Authors: Messina, Nicole L, Banks, Kellie M, Vidacs, Eva, Martin, Ben P, Long, Fennella, Christiansen, Ailsa J, Smyth, Mark J, Clarke, Christopher J P, Johnstone, Ricky W
• Format: Journal Article
• Language: English
• Published: United States Nature Publishing Group 01.10.2013; Blackwell Science Ltd
• Subjects: Animals; CD4-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - immunology; Cell Growth Processes - genetics; Cells, Cultured; Cytotoxicity, Immunologic; Gene Expression Regulation, Neoplastic; Humans; Killer Cells, Natural - immunology; Lymphocyte Depletion; Methylcholanthrene - toxicity; Mice; Mice, Inbred C57BL; Mice, Knockout; Monitoring, Immunologic; Neoplasm Transplantation; NK cells; Sarcoma, Experimental - chemically induced; Sarcoma, Experimental - immunology; signal transduction; Stat1; STAT1 Transcription Factor - genetics; STAT1 Transcription Factor - immunology; STAT1 Transcription Factor - metabolism; transcription factors; tumour immunity
• ISSN: 0818-9641; 1440-1711
• DOI: 10.1038/icb.2013.41

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.