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

Stefania Girlanda, Claudio Fortis, Daniela Belloni, Elisabetta Ferrero, Paolo Ticozzi, Clara Sciorati, Moreno Tresoldi, Aurelio Vicari, Thomas Spies, Veronika Groh, Federico Caligaris Cappio, Marina Ferrarini

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)7502-7508
Number of pages7
JournalCancer Research
Volume65
Issue number16
DOIs
Publication statusPublished - Aug 15 2005

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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