Glucocorticoid receptor activation induces NK cells to produce AREG and restricts their anti-tumor activity in skin cancer

Abstract

The interplay between natural killer (NK) cells and tumor microenvironment (TME) is closely associated with tumor progression. We showed NK cells are common constituents in the tissue of skin cancers including basal cell carcinoma (BCC), cutaneous squamous cell carcinoma (cSCC), extramammary paget disease (EMPD) and acral melanoma (aMM). scRNA-Seq revealed an inter and intra-tumor transcriptional heterogeneity of NK cells dependent on different skin TMEs. Unexpectedly, compared to peri-tumor, skin tumor NK cells down regulated the production of anti-tumor cytokines, IFN-γ and TNF-α, and up regulated the production of amphiregulin (AREG), a ligand of epidermal growth factor receptor (EGFR), which functions in promoting skin tumor growth and mediating immune tolerance. Mechanistically, skin TME upregulated NK cell glucocorticoid receptor (GR, NR3C1) activity, which specifically induced NK cell AREG production, and switched the anti-tumor characteristics of NK cells to a homeostatic feature. NR3C1 knockout or GR inhibitor abolished NK cell AREG production. Finally, we showed primary GR activation induced a memory response of AREG production by NK cells upon secondary stimuli, however pro-inflammatory cytokine induced memory response of IFN-γ production was inhibited by GR activation. These findings highlight the glucocorticoid receptor-NK cell-AREG axis may serve as a potential target for anti-cancer therapies.