TY - JOUR
T1 - MICA expressed by multiple myeloma and monoclonal gammopathy of undetermined significance plasma cells costimulates pamidronate-activated γδ lymphocytes
AU - Girlanda, Stefania
AU - Fortis, Claudio
AU - Belloni, Daniela
AU - Ferrero, Elisabetta
AU - Ticozzi, Paolo
AU - Sciorati, Clara
AU - Tresoldi, Moreno
AU - Vicari, Aurelio
AU - Spies, Thomas
AU - Groh, Veronika
AU - Cappio, Federico Caligaris
AU - Ferrarini, Marina
PY - 2005/8/15
Y1 - 2005/8/15
N2 - 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 γ9/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.
AB - 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 γ9/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.
UR - http://www.scopus.com/inward/record.url?scp=23844514335&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=23844514335&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-05-0731
DO - 10.1158/0008-5472.CAN-05-0731
M3 - Article
C2 - 16103105
AN - SCOPUS:23844514335
VL - 65
SP - 7502
EP - 7508
JO - Journal of Cancer Research
JF - Journal of Cancer Research
SN - 0008-5472
IS - 16
ER -