Loss of STAT3 in murine NK cells enhances NK cell-dependent tumor surveillance

The members of the signal transducer and activator of transcription (STAT) family of transcription factors modulate the development and function of natural killer (NK) cells. NK cell-mediated tumor surveillance is particularly important in the body's defense against hematological malignancies such as leukemia. STAT3 inhibitors are currently being developed, although their potential effects on NK cells are not clear. We have investigated the function of STAT3 in NK cells with Stat3(Delta/Delta) Ncr1-iCreTg mice, whose NK cells lack STAT3. In the absence of STAT3, NK cells develop normally and in normal numbers, but display alterations in the kinetics of interferon-gamma (IFN-gamma) production. We report that STAT3 directly binds the IFN-gamma promoter. In various in vivo models of hematological diseases, loss of STAT3 in NK cells enhances tumor surveillance. The reduced tumor burden is paralleled by increased expression of the activating receptor DNAM-1 and the lytic enzymes perforin and granzyme B. Our findings imply that STAT3 inhibitors will stimulate the cytolytic activity of NK cells against leukemia, thereby providing an additional therapeutic benefit.