Deletion of the mRNA endonuclease Regnase-1 promotes NK cell anti-tumor activity via OCT2-dependent transcription of Ifng.

Limited infiltration and activity of natural killer (NK) and T cells within the tumor microenvironment (TME) correlate with poor immunotherapy responses. Here, we examined the role of the endonuclease Regnase-1 on NK cell anti-tumor activity. NK cell-specific deletion of Regnase-1 (Reg1 ΔNK) augmented cytolytic activity and interferon-gamma (IFN-γ) production in vitro and increased intra-tumoral accumulation of Reg1 ΔNK-NK cells in vivo , reducing tumor growth dependent on IFN-γ. Transcriptional changes in Reg1 ΔNK-NK cells included elevated IFN-γ expression, cytolytic effectors, and the chemokine receptor CXCR6. IFN-γ induced expression of the CXCR6 ligand CXCL16 on myeloid cells, promoting further recruitment of Reg1 ΔNK-NK cells. Mechanistically, Regnase-1 deletion increased its targets, the transcriptional regulators OCT2 and IκBζ, following interleukin (IL)-12 and IL-18 stimulation, and the resulting OCT2-IκBζ-NF-κB complex induced Ifng transcription. Silencing Regnase-1 in human NK cells increased the expression of IFNG and POU2F2. Our findings highlight NK cell dysfunction in the TME and propose that targeting Regnase-1 could augment active NK cell persistence for cancer immunotherapy. [Display omitted] • Regnase-1 deficiency strengthens IFN-γ-mediated anti-tumor immunity of NK cells • IFN-γ-induced CXCL16 detains CXCR6+ mature NK cells in tumor microenvironment • Regnase-1-null NK cells induce a widespread increase in chromatin accessibility • The complex of OCT2, IκBζ, and NF-κB collaborates in the transcription of Ifng Low persistence and reduced activity of NK cells limit anti-tumor immunity. Sun, Nagahama, et al. find that NK cell-specific deficiency of the endonuclease Regnase-1 promotes NK cell persistence in the tumor microenvironment via continuous expression of CXCR6 and enhances anti-tumor activity through increased Ifng transcription mediated by OCT2. [ABSTRACT FROM AUTHOR]

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