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CDK8-mediated STAT1-S727 phosphorylation restrains NK cell cytotoxicity and tumor surveillance

Eva Maria Putz1, Dagmar Gotthardt, Gregor Hoermann

  • 1Institute of Pharmacology and Toxicology, Department for Biomedical Sciences, University of Veterinary Medicine Vienna, 1210 Vienna, Austria.

Cell Reports
|August 13, 2013
PubMed

Insights

Mutating a specific site on STAT1 enhances natural killer (NK) cell anti-tumor activity. This finding suggests targeting CDK8 could boost NK cell immunity against cancers like melanoma and leukemia.

Area of Science:

  • Immunology
  • Molecular Biology
  • Oncology

Background:

  • Natural killer (NK) cells are crucial for innate immunity against tumors and viral infections.
  • The transcription factor STAT1 plays a key role in NK cell function.
  • STAT1 phosphorylation at serine 727 (S727) influences NK cell activity.

Purpose of the Study:

  • To investigate the impact of mutating the STAT1 S727 phosphorylation site on NK cell function and anti-tumor immunity.
  • To explore the role of cyclin-dependent kinase 8 (CDK8) in STAT1 phosphorylation.
  • To evaluate the therapeutic potential of inhibiting CDK8 for cancer immunotherapy.

Main Methods:

  • Site-directed mutagenesis of STAT1 at S727 (Stat1-S727A).
  • Assessment of NK cell cytotoxicity against various tumor cell lines.
  • Measurement of perforin and granzyme B expression in NK cells.
  • In vivo studies using Stat1-S727A mice in tumor models (melanoma, leukemia, breast cancer).
  • Pharmacological inhibition of CDK8.

Main Results:

  • Mutation of Stat1-S727A significantly enhanced NK cell cytotoxicity.
  • Stat1-S727A mutation led to increased expression of cytotoxic effector molecules perforin and granzyme B.
  • Stat1-S727A mice exhibited delayed tumor progression in multiple cancer models.
  • Constitutive S727 phosphorylation was dependent on CDK8 activity.

Conclusions:

  • STAT1 phosphorylation at S727 negatively regulates NK cell cytotoxic function.
  • Targeting CDK8 to inhibit STAT1-S727 phosphorylation can enhance NK cell-mediated anti-tumor surveillance.
  • Inhibition of CDK8 represents a potential therapeutic strategy for augmenting anti-cancer immunity.

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