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

• Published in: Cancer research (Chicago, Ill.) Vol. 65; no. 16; pp. 7502 - 7508
• Main Authors: Girlanda, Stefania, Fortis, Claudio, Belloni, Daniela, Ferrero, Elisabetta, Ticozzi, Paolo, Sciorati, Clara, Tresoldi, Moreno, Vicari, Aurelio, Spies, Thomas, Groh, Veronika, Caligaris-Cappio, Federico, Ferrarini, Marina
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.08.2005
• Subjects: Antineoplastic agents; Biological and medical sciences; Chemotherapy; Hematologic and hematopoietic diseases; Immunodeficiencies. Immunoglobulinopathies; Immunoglobulinopathies; Immunopathology; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Medical sciences; Pharmacology. Drug treatments; Antineoplastic agent; Immunopathology; HLA-System; Diphosphonic acid derivatives; Malignant hemopathy; Plasmocyte; Myeloma; Bisphosphonates; Pamidronic acid; Monoclonal gammopathy of undetermined significance; Immunoglobulinopathy; Lymphoproliferative syndrome; T-Lymphocyte; Lymphocyte; Class I histocompatibility antigen
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-05-0731

Amino-biphosphonates (like pamidronate) activate human Vγ9/Vδ2 T lymphocytes and promote their cytotoxicity against multiple myeloma cells. T-cell receptor (TCR)–mediated effector functions of γδ 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-γ production by Vγ9/Vδ2 cells only upon pamidronate treatment, suggesting a dual interaction between Vγ9/Vδ2 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 γδ cells, as indicated by the significantly (P < 0.05) higher γδ 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 Vγ9/Vδ2 lymphocytes can be exploited in the immune therapy of early stages multiple myeloma and possibly of premalignant disease.