Authors: Subhashis Sarkar Michel van Gelder Willy Noort Yunping Xu Kasper M A Rouschop Richard Groen Harry C Schouten Marcel G J Tilanus Wilfred T V Germeraad Anton C M Martens Gerard M J Bos Lotte Wieten
Publish Date: 2015/04/29
Volume: 64, Issue: 8, Pages: 951-963
Abstract
Immunotherapy with allogeneic natural killer NK cells offers therapeutic perspectives for multiple myeloma patients Here we aimed to refine NK cell therapy by evaluation of the relevance of HLAclass I and HLAE for NK antimyeloma reactivity We show that HLAclass I was strongly expressed on the surface of patientderived myeloma cells and on myeloma cell lines HLAE was highly expressed by primary myeloma cells but only marginally by cell lines HLAElow expression on U266 cells observed in vitro was strongly upregulated after in vivo bone marrow growth in RAG2−/− γc−/− mice suggesting that in vitro HLAE levels poorly predict the in vivo situation Concurrent analysis of inhibitory receptors KIR2DL1 KIR2DL2/3 KIR3DL1 and NKG2A and NK cell degranulation upon coculture with myeloma cells revealed that KIR–ligandmismatched NK cells degranulate more than matched subsets and that HLAE abrogates degranulation of NKG2A+ subsets Inhibition by HLAclass I and HLAE was also observed with IL2activated NK cells and at low oxygen levels 06 mimicking hypoxic bone marrow niches where myeloma cells preferentially reside Our study demonstrates that NKG2Anegative KIR–ligandmismatched NK cells are the most potent subset for clinical application We envision that infusion of high numbers of this subclass will enhance clinical efficacy
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