MICA expressed by multiple myeloma and monoclonal gammopathy of undetermined significance plasma cells costimulates pamidronate-activated γδ lymphocytes

Amino-biphosphonates (like pamidronate) activate human V gamma 9/V delta 2 T lymphocytes and promote their cytotoxicity against multiple myeloma cells. T-cell receptor (TCR)-mediated effector functions of gamma delta 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-gamma production by V gamma 9/V delta 2 cells only upon pamidronate treatment, suggesting a dual interaction between V gamma 9V delta 2 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 gamma delta cells, as indicated by the significantly (P < 0.05) higher gamma delta 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 mycloma. Moreover, pamidronate-activated V gamma 9/V delta 2 lymphocytes can be exploited in the immune therapy of early stages multiple mycloma and possibly of premalignant disease.