KIR downregulation by IL-12/15/18 unleashes human NK cells from KIR/HLA-I inhibition and enhances killing of tumor cells

• Verfasst von: Ewen, Eva-Maria [VerfasserIn]
• Verfasst von: Pahl, Jens [VerfasserIn]
• Verfasst von: Cerwenka, Adelheid [VerfasserIn]
• Titel: KIR downregulation by IL-12/15/18 unleashes human NK cells from KIR/HLA-I inhibition and enhances killing of tumor cells
• Verf.angabe: Eva-Maria Ewen, Jens H.W. Pahl, Matthias Miller, Carsten Watzl, Adelheid Cerwenka
• Jahr: 2018
• Umfang: 11 S.
• Illustrationen: Diagramme
• Fussnoten: First published: 06 November 2017 ; Gesehen am 09.11.2018
• Titel Quelle: Enthalten in: European journal of immunology
• Ort Quelle: Weinheim : Wiley-VCH, 1971
• Jahr Quelle: 2018
• Band/Heft Quelle: 48(2018), 2, Seite 355-365
• ISSN Quelle: 1521-4141
• DOI: doi:10.1002/eji.201747128
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: Cancer immunotherapy
• Sach-SW: IL-12/15/18 activation
• Sach-SW: Killer cell immunoglobulin-like receptors (KIRs)
• Sach-SW: NK cell receptors
• Sach-SW: NK cells
• K10plus-PPN: 1582810850

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.