Enhancing NK cell-mediated tumor rejection by activation of the aryl hydrocarbon receptor (48.31)

Abstract

Abstract Natural killer (NK) cells’ tumoricidal effector activity is regulated by a balance of inhibitory and activating receptors. We demonstrate that murine NK cells express a cytoplasmic receptor called the aryl hydrocarbon receptor (AhR). AhR is upregulated upon NK cell activation and binds a wide range of endogenous and exogenous ligands. Upon binding agonistic ligands, this receptor translocates to the nucleus and regulates transcription. We show that activation of AhR in NK cells enhances IFNγ production by stimulated NK cells. Furthermore, activation of AhR in vivo results in enhanced rejection of RMA-S tumors in an NK cell - dependent and AhR - dependent manner. This rejection is correlated with an increase in tumor-infiltrating NK cells. Importantly, this rejection of RMA-S tumors is not the result of the AhR agonist’s effects on the tumor cells directly because RMA-S cells do not express AhR, and their proliferation rate in vivo is not affected by exposure to the ligands. This function of AhR as a potential enhancer of NK cell activity is likely to be physiologic because we also find that AhR-deficient mice are not able to control RMA-S tumors. We show that this defect is inherent to the NK cells themselves using an adoptive transfer approach. Thus, we conclude that AhR plays an important role in the modulation of NK cell effector functions and that activation of this receptor may be a novel therapeutic strategy for cancer treatment and prevention.