title: Novel B7-H4-mediated crosstalk between human non-Hodgkin lymphoma cells and tumor-associated macrophages leads to immune evasion via secretion of IL-6 and IL-10.
abstract: Non-Hodgkin lymphoma (NHL) is an incurable lymphoproliferative cancer, and patients with NHL have a poor prognosis. The present study explored the regulatory mechanism of expression and possible roles of the immunosuppressive B7-H4 molecule in human NHL. For functional studies, NHL-reactive T cell lines were generated via the isolation of allogeneic CD3+T cells from healthy donors and repeated in vitro stimulation with irradiated NHL cells isolated from patients. B7-H4 was found to be distributed in NHL cells and tissues, and its surface protein expression levels were further upregulated by the incubation of NHL cells with interleukin (IL)-6, IL-10, or interferon-γ. Additionally, the supernatants of tumor-associated macrophages (tMφs) upregulated B7-H4 surface expression by producing IL-6 and IL-10. B7-H4 expressed in NHL cells inhibited the cytotoxic activity of NHL-reactive T cells. Conversely, the inhibition of B7-H4 in NHL cells promoted T cell immunity and sensitized NHL cells to cytolysis. Furthermore, tMφs induced B7-H4 promoted NHL cell evasion of the T cell immune response. In conclusion, this study shows that NHL-expressed B7-H4 is an important immunosuppressive factor that inhibits host anti-tumor immunity to NHL. Targeting tumor-expressed B7-H4 may thus provide a new treatment strategy for NHL patients.
authors.affiliation: Central Laboratory, Linyi People's Hospital, Shandong University, Linyi, Shandong, China.|Department of Neurology, Shandong Provincial Hospital, Shandong University, 44 Wenhua West Road, Jinan, Shandong, China.|Department of Neurology, Linyi People's Hospital, Shandong University, Linyi, Shandong, China.
authors.forename: Fengyuan
authors.initials: F
authors.lastname: Che
authors.affiliation: Department of Neurosurgery, Linyi People's Hospital, Shandong University, Linyi, Shandong, China.
authors.forename: Xueyuan
authors.initials: X
authors.lastname: Heng
authors.affiliation: Department of Hematology, Linyi People's Hospital, Shandong University, No. 27 Jiefang Road, Lanshan District, Linyi, Shandong, China.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Central Laboratory, Linyi People's Hospital, Shandong University, Linyi, Shandong, China.
authors.forename: Quanping
authors.initials: Q
authors.lastname: Su
authors.affiliation: Hematology Laboratory, Linyi People's Hospital, Shandong University, Linyi, Shandong, China.
authors.forename: Baoxue
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Hematology Laboratory, Linyi People's Hospital, Shandong University, Linyi, Shandong, China.
authors.forename: Yanying
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Hematology Laboratory, Linyi People's Hospital, Shandong University, Linyi, Shandong, China.
authors.forename: Zhaohong
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Neurology, Shandong Provincial Hospital, Shandong University, 44 Wenhua West Road, Jinan, Shandong, China. duyf69@163.com.
authors.forename: Yifeng
authors.initials: Y
authors.lastname: Du
authors.affiliation: Department of Hematology, Linyi People's Hospital, Shandong University, No. 27 Jiefang Road, Lanshan District, Linyi, Shandong, China. wanglj730@163.com.|Hematology Laboratory, Linyi People's Hospital, Shandong University, Linyi, Shandong, China. wanglj730@163.com.
authors.forename: Lijuan
authors.initials: L
authors.lastname: Wang
mesh_terms: D002450:Cell Communication / Q000276:immunology; D006801:Humans; D016753:Interleukin-10 / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism*; D008228:Lymphoma, Non-Hodgkin / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D008264:Macrophages / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014407:Tumor Cells, Cultured; D019139:Tumor Escape; D060907:V-Set Domain-Containing T-Cell Activation Inhibitor 1 / Q000378:metabolism*
chemical_list: C508609:IL10 protein, human; C508600:IL6 protein, human; D015850:Interleukin-6; D060907:V-Set Domain-Containing T-Cell Activation Inhibitor 1; C475826:VTCN1 protein, human; D016753:Interleukin-10
keywords: B7-H4; IL-10; IL-6; Immune evasion; Non-Hodgkin lymphoma; Tumor-associated macrophages