PD-L1 is induced in hepatocytes by viral infection and by interferon-α and -γ and mediates T cell apoptosis

Mühlbauer, Marcus; Weiß, TS; Froh, Matthias; Schütz, Christian; Blank, Christian U.; Schölmerich, Jürgen; Hellerbrand, Claus

doi:10.1055/s-2006-931751

Cited by 51 publications

(64 citation statements)

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“…Primary murine and human hepatocytes, hepatic stellate cells (HSCs) and Kupffer cells were isolated and cultured as described 18 19. In vitro activation of HSCs was achieved by cell culture on uncoated tissue culture dishes 18.…”

Section: Methodsmentioning

confidence: 99%

Enhanced expression of BMP6 inhibits hepatic fibrosis in non-alcoholic fatty liver disease

Arndt

Wacker

Dorn

et al. 2014

Gut

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Section: Methodsmentioning

confidence: 99%

Enhanced expression of BMP6 inhibits hepatic fibrosis in non-alcoholic fatty liver disease

Arndt

Wacker

Dorn

et al. 2014

Gut

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“…In addition, expression of B7-H1 on hepatocytes was enhanced by activated T cells or viral infection, and hepatocytes related-B7-H1 can induce co-cultured T cell apoptosis in vitro (Mühlbauer et al, 2006).…”

Section: Stimulation Of B7-h1 In Hepatocarcinoma Cells By Hbx 767mentioning

confidence: 98%

“…For activation, T cells were incubated on PBS-washed anti-CD3-coated 96-well, round-bottomed plates (clone: OKT3, eBioscience, 100 μg/plate) with anti-CD28 (clone: CD28.2, eBioscience; 1 μg/ml/1 × 10 6 ) and rIL2 (PromoKine, Heidelberg, Germany; 100 IU/ml/1 × 10 6 ) (Mühlbauer et al, 2006).…”

Section: Cell Culture and Transfectionmentioning

confidence: 99%

“…Previous work has demonstrated that B7-H1 expressed on tumor cells increases T cell apoptosis (Dong et al, 2002;Mühlbauer et al, 2006). To detect the potential function of B7-H1 in T cell apoptosis, HBx + -HepG2 and HBx --HepG2 cells were co-cultured with activated T cells.…”

Section: Hbx-induced B7-h1 Signal Promotes Co-cultured T Cell Apoptosismentioning

confidence: 99%

“…In addition to mediate co-culture T cell apoptosis (Dong et al, 2002;Mühlbauer et al, 2006). B7-H1 functions as a receptor and reverse B7-H1 signaling on cancer cells refracts cell apoptosis (Azuma et al, 2008).…”

Section: Stimulation Of B7-h1 In Hepatocarcinoma Cells By Hbx 767mentioning

confidence: 99%

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Stimulation of B7-H1 in Hepatocarcinoma Cells by Hepatitis B virus X Antigen

Yang

Guo

et al. 2010

Immunological Investigations

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The cross-talk between the hepatitis B virus X protein (HBx) and B7-H1 in hepatocarcinoma (HCC) is unclear. This study analyzed the potential relationships between HBx and B7-H1 in hepatocarcinogenesis. One of human HCC cell lines, HepG2 cells, was transfected to stably express HBx protein (HBx(+)-HepG2). The transcription of B7-H1 mRNA was increased significantly in these cells compared to cells transfected with control vector (HBx(-)-HepG2), as confirmed by a comparative genome-wide microarray analysis (Capitalbio) and real time quantitative PCR (qPCR). Flow cytometry and western-blot further demonstrated that B7-H1 protein synthesis was enhanced in HBx(+)-HepG2 cells. Site-directed mutagenesis of promoter constructs revealed that the transcription factor (NF)-κB binding site between 128 and 137 bp upstream of B7-H1 gene transcriptional start site is primarily responsible for HBx-mediated B7-H1 expression. Co-culture experiments with HBx(+)-HepG2/T cells showed that the number of apoptotic T cells increased profoundly, and this effect could be partially prevented when a neutralizing mAb against B7-H1 was added to the culture, demonstrating that B7-H1 signaling can promote T cell apoptosis. Our results suggest that the expression of B7-H1 in hepatocarcimona cells can be initiated by HBx antigen, thus inducing T cell apoptosis and finally potentially facilitates the genesis of HCC.

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Chemotherapy induces tumor immune evasion by upregulation of programmed cell death ligand 1 expression in bone marrow stromal cells

Yang

Wang

et al. 2017

Molecular Oncology

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Programmed cell death ligand 1 (PD‐L1) is a negative regulator of the immune response that enables tumor cells to escape T‐cell immunity. Although PD‐L1 expression in cancer cells has been extensively studied, the expression of PD‐L1 in stromal cells and its clinical significance remain largely unknown. Here, we show that bone marrow stromal cells express a low level of PD‐L1 and that this molecule is significantly upregulated by key drugs used in the treatment of lymphoma at clinically relevant concentrations. Mechanistically, chemotherapeutic drugs induce PD‐L1 expression in stromal cells through upregulation of granulocyte macrophage colony‐stimulating factor and activation of the extracellular signal‐regulated kinase (ERK) 1/2 signaling pathway. Suppression of ERK by a chemical inhibitor or genetic silencing of ERK2 expression prevents drug‐induced PD‐L1 expression. PD‐L1 expression is upregulated in the bone marrow stromal cells of mice treated with doxorubicin and in drug‐treated bone marrow specimens from lymphoma patients. Drug‐induced PD‐L1 expression in stromal cells can cause significant impairment of T‐cell functions. Overall, our study reveals a previously unrecognized mechanism by which chemotherapy induces tumor immune evasion by upregulation of PD‐L1 in bone marrow stromal cells, and provides new evidence for the combination of chemotherapy and anti‐PD‐L1/PD‐1 as an effective strategy for treatment of lymphoma and other cancers.

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PD-L1 is induced in hepatocytes by viral infection and by interferon-α and -γ and mediates T cell apoptosis

Cited by 51 publications

References 0 publications

Enhanced expression of BMP6 inhibits hepatic fibrosis in non-alcoholic fatty liver disease

Enhanced expression of BMP6 inhibits hepatic fibrosis in non-alcoholic fatty liver disease

Stimulation of B7-H1 in Hepatocarcinoma Cells by Hepatitis B virus X Antigen

Chemotherapy induces tumor immune evasion by upregulation of programmed cell death ligand 1 expression in bone marrow stromal cells

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