title: MICA expressed by multiple myeloma and monoclonal gammopathy of undetermined significance plasma cells Costimulates pamidronate-activated gammadelta lymphocytes.
abstract: Amino-biphosphonates (like pamidronate) activate human Vgamma9/Vdelta2 T lymphocytes and promote their cytotoxicity against multiple myeloma cells. T-cell receptor (TCR)-mediated effector functions of gammadelta 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 Vgamma9/Vdelta2 cells only upon pamidronate treatment, suggesting a dual interaction between Vgamma9/Vdelta2 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 gammadelta cells, as indicated by the significantly (P < 0.05) higher gammadelta 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 Vgamma9/Vdelta2 lymphocytes can be exploited in the immune therapy of early stages multiple myeloma and possibly of premalignant disease.
authors.affiliation: Laboratory of Tumor Immunology and Department of Oncology, Istituto di Ricerca e Cura a Carattere Scientifico H.S. Raffaele, Milan, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Girlanda
authors.forename: Claudio
authors.initials: C
authors.lastname: Fortis
authors.forename: Daniela
authors.initials: D
authors.lastname: Belloni
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Ferrero
authors.forename: Paolo
authors.initials: P
authors.lastname: Ticozzi
authors.forename: Clara
authors.initials: C
authors.lastname: Sciorati
authors.forename: Moreno
authors.initials: M
authors.lastname: Tresoldi
authors.forename: Aurelio
authors.initials: A
authors.lastname: Vicari
authors.forename: Thomas
authors.initials: T
authors.lastname: Spies
authors.forename: Veronika
authors.initials: V
authors.lastname: Groh
authors.forename: Federico
authors.initials: F
authors.lastname: Caligaris-Cappio
authors.forename: Marina
authors.initials: M
authors.lastname: Ferrarini
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology; D004164:Diphosphonates / Q000494:pharmacology*; D005260:Female; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis* / Q000276:immunology; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D008798:Mevalonic Acid / Q000276:immunology / Q000378:metabolism; D008875:Middle Aged; D009101:Multiple Myeloma / Q000276:immunology*; D000077268:Pamidronate; D010265:Paraproteinemias / Q000276:immunology*; D010950:Plasma Cells / Q000276:immunology*; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D000970:Antineoplastic Agents; D004164:Diphosphonates; D015395:Histocompatibility Antigens Class I; C099187:MHC class I-related chain A; D016692:Receptors, Antigen, T-Cell, gamma-delta; D000077268:Pamidronate; D008798:Mevalonic Acid