Optimal selection of natural killer cells to kill myeloma: the role of HLA-E and NKG2A

• Published in: Cancer Immunology, Immunotherapy Immunotherapy, 2015-08, Vol.64 (8), p.951-963
• Main Authors: Sarkar, Subhashis, van Gelder, Michel, Noort, Willy, Xu, Yunping, Rouschop, Kasper M. A., Groen, Richard, Schouten, Harry C., Tilanus, Marcel G. J., Germeraad, Wilfred T. V., Martens, Anton C. M., Bos, Gerard M. J., Wieten, Lotte
• Format: Article
• Language: English
• Subjects: Animals; Bone marrow; Cancer Research; Cancer therapies; Cell Degranulation; Cell Line, Tumor; Cell Separation - methods; Coculture Techniques; Cytotoxicity, Immunologic; DNA-Binding Proteins - genetics; Flow Cytometry; Graft versus host disease; Hematology; Histocompatibility Antigens Class I - immunology; HLA-E Antigens; Humans; Immunoglobulins; Immunology; Immunotherapy; Immunotherapy - methods; Interleukin-2 - immunology; Killer Cells, Natural - immunology; Killer Cells, Natural - transplantation; Leukemia; Medicine; Medicine & Public Health; Mice; Mice, Knockout; Multiple myeloma; Multiple Myeloma - immunology; Multiple Myeloma - therapy; Neoplasm Transplantation; NK Cell Lectin-Like Receptor Subfamily C - immunology; Oncology; Original; Original Article; Oxygen - metabolism; Patients; Stem cell transplantation
• ISSN: 0340-7004; 1432-0851
• DOI: 10.1007/s00262-015-1694-4

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 HLA-class I and HLA-E for NK anti-myeloma reactivity. We show that HLA-class I was strongly expressed on the surface of patient-derived myeloma cells and on myeloma cell lines. HLA-E was highly expressed by primary myeloma cells but only marginally by cell lines. HLA-E low expression on U266 cells observed in vitro was strongly upregulated after in vivo (bone marrow) growth in RAG-2 −/− γ c −/− mice, suggesting that in vitro HLA-E levels poorly predict the in vivo situation. Concurrent analysis of inhibitory receptors (KIR2DL1, KIR2DL2/3, KIR3DL1 and NKG2A) and NK cell degranulation upon co-culture with myeloma cells revealed that KIR–ligand-mismatched NK cells degranulate more than matched subsets and that HLA-E abrogates degranulation of NKG2A+ subsets. Inhibition by HLA-class I and HLA-E was also observed with IL-2-activated NK cells and at low oxygen levels (0.6 %) mimicking hypoxic bone marrow niches where myeloma cells preferentially reside. Our study demonstrates that NKG2A-negative, KIR–ligand-mismatched NK cells are the most potent subset for clinical application. We envision that infusion of high numbers of this subclass will enhance clinical efficacy.