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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

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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.

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Abbreviations

CTL:

Cytotoxic T lymphocyte

DLBCL:

Diffuse large B cell lymphoma

FasL:

Fas ligand

FL:

Follicular lymphoma

IFN:

Interferon

IL:

Interleukin

IgG:

Immunoglobulin G

LPS:

Lipopolysaccharide

Ly10:

OCI-Ly10

mAb:

Monoclonal antibody

M-CSF:

Macrophage colony-stimulating factor

MHC:

Major histocompatibility complex

Nal:

Nalmawa

NHL:

Non-Hodgkin lymphoma

nMφs:

Normal macrophages

PBMCs:

Peripheral blood mononuclear cells

PD:

Programmed death protein

PD-L:

Programmed death ligand

TGF:

Transforming growth factor

tMφs:

Tumor-associated macrophages

TNF:

Tumor necrosis factor

Tregs:

Regulatory T cells

VEGF:

Vascular endothelial growth factor

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Authors and Affiliations

  1. Central Laboratory, Linyi People’s Hospital, Shandong University, Linyi, Shandong, China

    Fengyuan Che & Quanping Su

  2. Department of Neurology, Shandong Provincial Hospital, Shandong University, 44 Wenhua West Road, Jinan, Shandong, China

    Fengyuan Che & Yifeng Du

  3. Department of Neurology, Linyi People’s Hospital, Shandong University, Linyi, Shandong, China

    Fengyuan Che

  4. Department of Neurosurgery, Linyi People’s Hospital, Shandong University, Linyi, Shandong, China

    Xueyuan Heng

  5. Department of Hematology, Linyi People’s Hospital, Shandong University, No. 27 Jiefang Road, Lanshan District, Linyi, Shandong, China

    Haiyan Zhang & Lijuan Wang

  6. Hematology Laboratory, Linyi People’s Hospital, Shandong University, Linyi, Shandong, China

    Baoxue Zhang, Yanying Chen, Zhaohong Zhang & Lijuan Wang

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  1. Fengyuan Che
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Correspondence to Yifeng Du or Lijuan Wang.

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Funding

This work was supported by Funds for Young Scholars of the National Natural Science Foundation of China (Grant No. 81402353), the Medical Health Science and Technology Development Plan of Shandong Province (Grant No. 2014WS0287), the China Postdoctoral Science Foundation (Grant No. 2015M580594), the Postdoctoral Innovation Foundation of Shandong Province (Grant No. 201502008), the Key Research Project program of Shandong Province (Grant No. 2016GSF201056), and the Natural Science Foundation of Shandong Province (Grant No. ZR2014HM077).

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Che, F., Heng, X., Zhang, H. et al. 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. Cancer Immunol Immunother 66, 717–729 (2017). https://doi.org/10.1007/s00262-017-1961-7

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