CDK8-Mediated STAT1-S727 Phosphorylation Restrains NK Cell Cytotoxicity and Tumor Surveillance

• Constitutive STAT1-S727 phosphorylation inhibits NK cell cytotoxicity
• Stat1-S727A NK cells are highly cytotoxic against tumor cells
• Stat1-S727A mice are more resistant to NK cell-surveilled tumors
• CDK8 phosphorylates STAT1-S727 in NK cells and restrains their cytotoxicity

SummaryThe transcription factor STAT1 is important in natural killer (NK) cells, which provide immediate defense against tumor and virally infected cells. We show that mutation of a single phosphorylation site (Stat1-S727A) enhances NK cell cytotoxicity against a range of tumor cells, accompanied by increased expression of perforin and granzyme B. Stat1-S727A mice display significantly delayed disease onset in NK cell-surveilled tumor models including melanoma, leukemia, and metastasizing breast cancer. Constitutive phosphorylation of S727 depends on cyclin-dependent kinase 8 (CDK8). Inhibition of CDK8-mediated STAT1-S727 phosphorylation may thus represent a therapeutic strategy for stimulating NK cell-mediated tumor surveillance.

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