KIR downregulation by IL‐12/15/18 unleashes human NK cells from KIR/HLA‐I inhibition and enhances killing of tumor cells. Issue 2 (29th November 2017)

• Record Type: Journal Article
• Authors: Ewen, Eva‐Maria; Pahl, Jens H.W.; Miller, Matthias; Watzl, Carsten; Cerwenka, Adelheid
• Is Part Of: European journal of immunology. Volume 48:Issue 2(2018)
• Page Start: 355
• Page End: 365
• Publication Date: 2017-11-29
• Subjects: Cancer immunotherapy -- IL‐12/15/18 activation -- Killer cell immunoglobulin‐like receptors (KIRs) -- NK cells -- NK cell receptors; Immunology -- Periodicals; 616.079
• DOI: 10.1002/eji.201747128
• Languages: English
• ISSNs: 0014-2980

Abstract

Abstract: To exploit autologous NK cells for cancer immunotherapy, it is highly relevant to circumvent killer cell immunoglobulin‐like receptor (KIR)‐mediated self‐inhibition of human NK cells by HLA‐I–expressing tumor cells. Here, we show that stimulation of NK cells with IL‐12/15/18 for two days led to downregulation of surface expression of the inhibitory KIR2DL2/L3, KIR2DL1 and KIR3DL1 receptors on peripheral blood NK cells. Downregulation of KIR expression was attributed to decreased KIR mRNA levels which could be re‐induced already 3 days after re‐culture in IL‐2. Reduced KIR2DL2/L3 expression on IL‐12/15/18–activated NK cells resulted in less inhibition upon antibody‐mediated KIR engagement and increased CD16‐dependent cytotoxicity in redirected lysis assays. Most importantly, downregulated KIR2DL2/L3 expression enabled enhanced cytotoxicity of IL‐12/15/18–stimulated NK cells against tumor cells expressing cognate HLA‐I molecules. NK cells pre‐activated with IL‐12/15/18 were previously shown to exert potent anti‐tumor activity and memory‐like long‐lived functionality, mediating remission in a subset of acute myeloid leukemia (AML) patients in a clinical trial. Our study reveals a novel mechanism of IL‐12/15/18 in improving the cytotoxicity of NK cells by reducing their sensitivity to inhibition by self–HLA‐I due to decreased KIR expression, highlighting the potency of IL‐12/15/18–activated NK cells for anti‐tumor immunotherapy protocols. Abstract : Stimulation of human NK cells with IL‐12/15/18 induced transient downregulation of surface expression and mRNA levels of inhibitory killer immunoglobulin‐like receptors (KIRs). Reduced KIR expression translated into enhanced NK cytotoxicity against cognate HLA‐I–expressing tumor cells, highlighting the potency of IL‐12/15/18–activated NK cells for anti‐tumor immunotherapy protocols.