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Blood, 1 January 2005, Vol. 105, No. 1, pp. 251-258.
Prepublished online as a Blood First Edition Paper on August 24, 2004; DOI 10.1182/blood-2004-04-1422.
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IMMUNOBIOLOGY
HLA class I, NKG2D, and natural cytotoxicity receptors regulate multiple myeloma cell recognition by natural killer cells
Ennio Carbone,
Paola Neri,
Maria Mesuraca,
Mariateresa T. Fulciniti,
Takemi Otsuki,
Daniela Pende,
Veronika Groh,
Thomas Spies,
Giuditta Pollio,
David Cosman,
Lucio Catalano,
Pierfrancesco Tassone,
Bruno Rotoli, and
Salvatore Venuta
From the Dipartimento di Medicina Sperimentale e Clinica " G. Salvatore," Università degli Studi di Catanzaro "Magna Graecia," Catanzaro, Italy; the Microbiology and Tumorbiology Center, Karolinska Institutet, Stockholm, Sweden; the Department of Hygiene, Kawasaki Medical School, Okayama, Japan; the Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy; the Fred Hutchinson Cancer Research Center, Seattle, WA; the Dipartimento di Medicina Clinica e Sperimentale, Università degli Studi di Napoli "Federico II," Napoli, Italy; and Amgen, Seattle, WA.
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 lectinlike 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. (Blood. 2005;105:251-258)
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