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MICA Expressed by Multiple Myeloma and Monoclonal Gammopathy of Undetermined Significance Plasma Cells Costimulates Pamidronate-Activated Lymphocytes

¹ Laboratory of Tumor Immunology and Department of Oncology; ² Laboratory of Clinical Immunology, Clinic of Infectious Diseases; ³ Dipartimento di Ricerca Biologica e Tecnologica; ⁴ Clinical Immunology and Rheumatology Unit, Istituto di Ricerca e Cura a Carattere Scientifico H.S. Raffaele; ⁵ Vita-Salute S. Raffaele University School of Medicine; ⁶ Institute of General Pathology and Center for Studies on Cellular Pathology of the Consiglio Nazionale delle Ricerche, Milan, Italy; and ⁷ Fred Hutchinson Cancer Research Center, Clinical Research Division, Seattle, Washington

Requests for reprints: Marina Ferrarini, Laboratory of Tumor Immunology, Istituto di Ricerca e Cura a Carattere Scientifico H.S. Raffaele, via Olgettina 60, I-20132 Milan, Italy. Phone: 39-02-2643-2612; Fax: 39-02-2643-2611; E-mail: ferrarini.marina{at}hsr.it.

Amino-biphosphonates (like pamidronate) activate human V9/V2 T lymphocytes and promote their cytotoxicity against multiple myeloma cells. T-cell receptor (TCR)–mediated effector functions of cells are enhanced upon triggering of the activating receptor NKG2D by MICA, a stress-inducible antigen expressed by epithelial and some hematopoietic tumors, including multiple myeloma. Here we show that MICA was expressed not only by myeloma cell lines and by 6 of 10 primary multiple myeloma cells from patients but also by bone marrow plasma cells from all (six of six) patients with preneoplastic gammopathy (monoclonal gammopathy of undetermined significance, MGUS), a direct precursor of multiple myeloma. Moreover, compared with multiple myeloma plasma cells, MICA was expressed by MGUS plasma cells at significantly (P < 0.05) higher levels. MICA expressed by myeloma cell lines contributed to killing and IFN- production by V9/V2 cells only upon pamidronate treatment, suggesting a dual interaction between V9/V2 lymphocytes and multiple myeloma plasma cells involving both TCR triggering and NKG2D-mediated signals. Finally, MICA enhanced killing of freshly derived, pamidronate-treated multiple myeloma cells from patients by cells, as indicated by the significantly (P < 0.05) higher cytotoxicity against MICA-positive rather than MICA-negative multiple myeloma cells. Our results indicate that MICA expressed by monoclonal plasma cells is functional and correlates with disease stages, suggesting a role for the molecule in the immune surveillance against multiple myeloma. Moreover, pamidronate-activated V9/V2 lymphocytes can be exploited in the immune therapy of early stages multiple myeloma and possibly of premalignant disease.

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