Modulation of antitumour immune responses by intratumoural Stat1 expression.

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. [ABSTRACT FROM AUTHOR]