Optimal selection of natural killer cells to kill myeloma: the role of HLA-E and NKG2A.
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(-/-) γc(-/-) 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.
Division of Hematology, Department of Internal Medicine, Maastricht University Medical Center+, Maastricht, The Netherlands.
Subhashis
S
Sarkar
Michel
M
van Gelder
Willy
W
Noort
Yunping
Y
Xu
Kasper M A
KM
Rouschop
Richard
R
Groen
Harry C
HC
Schouten
Marcel G J
MG
Tilanus
Wilfred T V
WT
Germeraad
Anton C M
AC
Martens
Gerard M J
GM
Bos
Lotte
L
Wieten
D000818:Animals; D015550:Cell Degranulation; D045744:Cell Line, Tumor; D002469:Cell Separation / Q000379:methods*; D018920:Coculture Techniques; D003602:Cytotoxicity, Immunologic; D004268:DNA-Binding Proteins / Q000235:genetics; D005434:Flow Cytometry; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D007376:Interleukin-2 / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology* / Q000637:transplantation*; D051379:Mice; D018345:Mice, Knockout; D009101:Multiple Myeloma / Q000276:immunology / Q000628:therapy*; D055654:NK Cell Lectin-Like Receptor Subfamily C / Q000276:immunology*; D009368:Neoplasm Transplantation; D010100:Oxygen / Q000378:metabolism; D000097625:HLA-E Antigens
D004268:DNA-Binding Proteins; D015395:Histocompatibility Antigens Class I; D007376:Interleukin-2; D055654:NK Cell Lectin-Like Receptor Subfamily C; D010100:Oxygen; D000097625:HLA-E Antigens; C064655:V(D)J recombination activating protein 2