MICA Expressed by Multiple Myeloma and Monoclonal Gammopathy of Undetermined Significance Plasma Cells Costimulates Pamidronate-Activated γδ Lymphocytes

Abstract

Amino-biphosphonates (like pamidronate) activate human V;9/VD2 T lymphocytes and promote their cytotoxicity against multiple myeloma cells. T-cell receptor (TCR)-mediated effector functions of ;D 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-; production by V;9/VD2 cells only upon pamidronate treatment, suggesting a dual interaction between V;9/VD2 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 ;D cells, as indicated by the significantly (P < 0.05) higher ;D 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 V;9/VD2 lymphocytes can be exploited in the immune therapy of early stages multiple myeloma and possibly of premalignant disease. (Cancer Res 2005; 65(16): 7502-8)

Increased sMICA and TGFβ 1 levels in HNSCC patients impair NKG2D-dependent functionality of activated NK cells

“…Tumor-specific stress ligands that stimulate or inhibit effector cells are adequate molecular markers of solid tumor prognosis. 26,27 For example, in a study by Wu et al, a significant correlation was found between high sMICA levels and prostate cancer disease progression. 18 Moreover, a strong association between cancer stage and metastasis, and a marked rise in soluble MICA and MICB levels was recently demonstrated in a large study of 512 patients with various malignancies.…”

Expression of T-plastin, FoxP3 and other tumor-associated markers by leukemic T-cells of cutaneous T-cell lymphoma

“…Because Mic-B protein expression by neoplastic T-cells was not studied nor was soluble Mic-B measured in the sera of our patients, we can only speculate as to the clinical significance of high Mic-B gene expression by neoplastic T-cells. However, assuming that high gene transcript levels indicate that Mic-B protein is being expressed as occurs with a variety of other malignancies including hematopoietic tumors [56][57][58], then the question arises how are these cells able to evade killing by NKG2D bearing NK or CD8+ T-cells considering the fact that NK cells harvested from patients with SS are capable of killing autologous neoplastic cells [30][31]. One potential mechanism is that the prolonged encounter with tumor cell-bound, but not soluble, NKG2D ligand alters NKG2D signalling in NK cells [59].…”

Redox homeostasis modulates the sensitivity of myeloma cells to bortezomib

“…Samples were taken at the time of diagnosis, prior to therapy. BM mononuclear cells were isolated by density centrifugation (Ficoll-Hypaque, Pharmacia, Piscataway, NJ, USA) as previously described (Girlanda et al, 2005), and depleted of stromal cells by adhesion to tissue culture dishes. Plasma cells were identified by flow cytometry analysis for CD138 expression and light scattering parameters.…”