Marrow stromal cells induce B7-H1 expression on myeloma cells, generating aggressive characteristics in multiple myeloma

• DOI: 10.1038/leu.2012.213
• Publication Date: 2012-07-25T06:39:13Z
• Authors: H Tamura; M Ishibashi; T Yamashita; S Tanosaki; N Okuyama; A Kondo; H Hyodo; E Shinya; H Takahashi; H Dong; K Tamada; L Chen; K Dan; K Ogata
• Keywords: Fas Ligand Protein; Interleukin-6; Reverse Transcriptase Polymerase Chain Reaction; Blotting, Western; Apoptosis; Flow Cytometry; Lymphocyte Activation; Real-Time Polymerase Chain Reaction; B7-H1 Antigen; 3. Good health; 03 medical and health sciences; 0302 clinical medicine; Proto-Oncogene Proteins c-bcl-2; Drug Resistance, Neoplasm; Tumor Cells, Cultured; Humans; RNA, Messenger; Neoplasm Recurrence, Local; Stromal Cells; Multiple Myeloma; Cell Proliferation; T-Lymphocytes, Cytotoxic

Tumor-associated B7-H1 molecules inhibit antitumor immunity in some malignancies. We found that B7-H1 expression on patient myeloma cells and human myeloma cell lines (HMCLs) was upregulated by cultivating the cells with autologous stromal cells and the human stromal cell line HS-5. Among major cytokines produced by HS-5 cells, interleukin (IL)-6-induced B7-H1 expression on HMCLs. Moreover, HS-5 cell-mediated B7-H1 expression was downregulated by inhibiting IL-6. B7-H1(+) HMCLs were more proliferative and less susceptible to antimyeloma chemotherapy compared with B7-H1(-) HMCLs. Moreover, the former cells showed higher levels of Bcl-2 and FasL expression than the latter. Finally, B7-H1 molecules on HMCLs induced T-cell apoptosis and anergy of tumor-specific T cells. Consistent with these in vitro observations, patients whose myeloma cells expressed high levels of B7-H1 had higher myeloma cell percentages in the bone marrow (BM) and higher serum lactate dehydrogenase levels compared with other myeloma patients. In addition, B7-H1 expression levels were often upregulated after myeloma patients relapsed or became refractory to therapy. Our data indicate that the BM microenvironment upregulates B7-H1 expression on myeloma cells, which links to the two biological actions of inducing T-cell downregulation and enhancing aggressive myeloma-cell characteristics. Modulating the B7-H1 pathway may be worthwhile in myeloma.