RRC ID 43969
Author Tamura H, Ishibashi M, Yamashita T, Tanosaki S, Okuyama N, Kondo A, Hyodo H, Shinya E, Takahashi H, Dong H, Tamada K, Chen L, Dan K, Ogata K.
Title Marrow stromal cells induce B7-H1 expression on myeloma cells, generating aggressive characteristics in multiple myeloma.
Journal Leukemia
Abstract 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.
Volume 27(2)
Pages 464-72
Published 2013-2-1
DOI 10.1038/leu.2012.213
PII leu2012213
PMID 22828443
MeSH Apoptosis B7-H1 Antigen / genetics B7-H1 Antigen / metabolism* Blotting, Western Cell Proliferation Drug Resistance, Neoplasm* Fas Ligand Protein / genetics Fas Ligand Protein / metabolism Flow Cytometry Humans Interleukin-6 / genetics Interleukin-6 / metabolism Lymphocyte Activation Multiple Myeloma / drug therapy Multiple Myeloma / metabolism Multiple Myeloma / pathology* Neoplasm Recurrence, Local / drug therapy Neoplasm Recurrence, Local / metabolism Neoplasm Recurrence, Local / pathology* Proto-Oncogene Proteins c-bcl-2 / genetics Proto-Oncogene Proteins c-bcl-2 / metabolism RNA, Messenger / genetics Real-Time Polymerase Chain Reaction Reverse Transcriptase Polymerase Chain Reaction Stromal Cells / immunology Stromal Cells / metabolism Stromal Cells / pathology* T-Lymphocytes, Cytotoxic / immunology* Tumor Cells, Cultured
IF 8.665
Times Cited 132
Human and Animal Cells PCM6(RCB1460)