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

doi:10.1158/0008-5472.CAN-05-0731

Cancer Health Disparities Conference 2009

Immunology

MICA Expressed by Multiple Myeloma and Monoclonal Gammopathy of Undetermined Significance Plasma Cells Costimulates Pamidronate-Activated ${gamma}$ ${delta}$ Lymphocytes

Stefania Girlanda¹^,5, Claudio Fortis², Daniela Belloni⁶, Elisabetta Ferrero¹, Paolo Ticozzi⁶, Clara Sciorati³, Moreno Tresoldi⁴, Aurelio Vicari¹, Thomas Spies⁷, Veronika Groh⁷, Federico Caligaris-Cappio¹^,5 and Marina Ferrarini¹

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 V ${gamma}$ 9/V ${delta}$ 2T lymphocytes and promote their cytotoxicity against multiplemyeloma cells. T-cell receptor (TCR)–mediated effectorfunctions of ${gamma}$ ${delta}$ cells are enhanced upon triggering of the activatingreceptor NKG2D by MICA, a stress-inducible antigen expressedby epithelial and some hematopoietic tumors, including multiplemyeloma. Here we show that MICA was expressed not only by myelomacell lines and by 6 of 10 primary multiple myeloma cells frompatients but also by bone marrow plasma cells from all (sixof six) patients with preneoplastic gammopathy (monoclonal gammopathyof undetermined significance, MGUS), a direct precursor of multiplemyeloma. 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 linescontributed to killing and IFN- ${gamma}$ production by V ${gamma}$ 9/V ${delta}$ 2 cells onlyupon pamidronate treatment, suggesting a dual interaction betweenV ${gamma}$ 9/V ${delta}$ 2 lymphocytes and multiple myeloma plasma cells involvingboth TCR triggering and NKG2D-mediated signals. Finally, MICAenhanced killing of freshly derived, pamidronate-treated multiplemyeloma cells from patients by ${gamma}$ ${delta}$ cells, as indicated by the significantly(P < 0.05) higher ${gamma}$ ${delta}$ cytotoxicity against MICA-positive ratherthan MICA-negative multiple myeloma cells. Our results indicatethat MICA expressed by monoclonal plasma cells is functionaland correlates with disease stages, suggesting a role for themolecule in the immune surveillance against multiple myeloma.Moreover, pamidronate-activated V ${gamma}$ 9/V ${delta}$ 2 lymphocytes can be exploitedin the immune therapy of early stages multiple myeloma and possiblyof premalignant disease.

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