Modulation of antitumour immune responses by intratumoural Stat1 expression

Immunol Cell Biol. 2013 Oct;91(9):556-67. doi: 10.1038/icb.2013.41. Epub 2013 Aug 20.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • STAT1 Transcription Factor / genetics
  • STAT1 Transcription Factor / immunology
  • STAT1 Transcription Factor / metabolism*
  • Sarcoma, Experimental / chemically induced
  • Sarcoma, Experimental / immunology*

Substances

  • STAT1 Transcription Factor
  • Methylcholanthrene