HLA class I, NKG2D, and natural cytotoxicity receptors regulate multiple myeloma cell recognition by natural killer cells.
The role of natural killer (NK) cells in multiple myeloma is not fully understood. Here, NK susceptibility of myeloma cells derived from distinct disease stages was evaluated in relation to major histocompatibility complex (MHC) class I, MHC class I chain-related protein A (MICA), MHC class I chain-related protein B (MICB), and UL16 binding protein (ULBP) expression. MHC class I molecules were hardly detectable on bone marrow cells of early-stage myeloma, while late-stage pleural effusion-derived cell lines showed a strong MHC class I expression. Conversely, a high MICA level was found on bone marrow myeloma cells, while it was low or not measurable on pleural effusion myeloma cells. The reciprocal surface expression of these molecules on bone marrow- and pleural effusion-derived cell was confirmed at mRNA levels. While bone marrow-derived myeloma cells were readily recognized by NK cells, pleural effusion-derived lines were resistant. NK protection of pleural effusion cells was MHC class I dependent. Receptor blocking experiments demonstrated that natural cytotoxicity receptor (NCR) and NK receptor member D of the lectin-like receptor family (NKG2D) were the key NK activating receptors for bone marrow-derived myeloma cell recognition. In ex vivo experiments patient's autologous fresh NK cells recognized bone marrow-derived myeloma cells. Our data support the hypothesis that NK cell cytotoxicity could sculpture myeloma and represents an important immune effector mechanism in controlling its intramedullary stages.
Carbone
Ennio
E
Dipartimento di Medicina Sperimentale e Clinica G. Salvatore, Università di Catanzaro Magna Graecia, Catanzaro, Italy. ennio.carbone@mtc.ki.se
Neri
Paola
P
Mesuraca
Maria
M
Fulciniti
Mariateresa T
MT
Otsuki
Takemi
T
Pende
Daniela
D
Groh
Veronika
V
Spies
Thomas
T
Pollio
Giuditta
G
Cosman
David
D
Catalano
Lucio
L
Tassone
Pierfrancesco
P
Rotoli
Bruno
B
Venuta
Salvatore
S
D036541:ADP-ribosyl Cyclase / Q000276:immunology; D051997:ADP-ribosyl Cyclase 1; D000368:Aged; D015703:Antigens, CD / Q000276:immunology; D019046:Bone Marrow Neoplasms / Q000276:immunology / Q000473:pathology; D002352:Carrier Proteins / Q000378:metabolism; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D005260:Female; D058851:GPI-Linked Proteins; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007694:Killer Cells, Natural / Q000276:immunology*; D008297:Male; D008562:Membrane Glycoproteins / Q000276:immunology; D008565:Membrane Proteins; D008875:Middle Aged; D009101:Multiple Myeloma / Q000235:genetics / Q000276:immunology*; D055655:NK Cell Lectin-Like Receptor Subfamily K; D055627:Natural Cytotoxicity Triggering Receptor 1; D016066:Pleural Effusion, Malignant / Q000276:immunology; D011509:Proteoglycans / Q000276:immunology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011971:Receptors, Immunologic / Q000276:immunology / Q000378:metabolism*; D055607:Receptors, Natural Killer Cell; D053667:Syndecans; D014407:Tumor Cells, Cultured
D015703:Antigens, CD; D002352:Carrier Proteins; D058851:GPI-Linked Proteins; D015395:Histocompatibility Antigens Class I; D047908:Intracellular Signaling Peptides and Proteins; C527085:KLRK1 protein, human; C099187:MHC class I-related chain A; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; C112260:NCR1 protein, human; D055655:NK Cell Lectin-Like Receptor Subfamily K; D055627:Natural Cytotoxicity Triggering Receptor 1; D011509:Proteoglycans; D012333:RNA, Messenger; D011971:Receptors, Immunologic; D055607:Receptors, Natural Killer Cell; D053667:Syndecans; C423231:ULBP1 protein, human; D036541:ADP-ribosyl Cyclase; C498154:CD38 protein, human; D051997:ADP-ribosyl Cyclase 1