title: Marrow stromal cells induce B7-H1 expression on myeloma cells, generating aggressive characteristics in multiple myeloma.
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.
authors: Department of Medicine, Division of Hematology, Nippon Medical School, Tokyo, Japan.
authors: H
authors: H
authors: Tamura
authors: M
authors: M
authors: Ishibashi
authors: T
authors: T
authors: Yamashita
authors: S
authors: S
authors: Tanosaki
authors: N
authors: N
authors: Okuyama
authors: A
authors: A
authors: Kondo
authors: H
authors: H
authors: Hyodo
authors: E
authors: E
authors: Shinya
authors: H
authors: H
authors: Takahashi
authors: H
authors: H
authors: Dong
authors: K
authors: K
authors: Tamada
authors: L
authors: L
authors: Chen
authors: K
authors: K
authors: Dan
authors: K
authors: K
authors: Ogata
mesh_terms: D017209:Apoptosis; D060890:B7-H1 Antigen / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm; D053222:Fas Ligand Protein / Q000235:genetics / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D008213:Lymphocyte Activation; D009101:Multiple Myeloma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017154:Stromal Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014407:Tumor Cells, Cultured
chemical_list: D060890:B7-H1 Antigen; C423236:CD274 protein, human; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D015850:Interleukin-6; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger