Dendritic cells with an increased PD-L1 by TGF-β induce T cell anergy for the cytotoxicity of hepatocellular carcinoma cells

Song, Shasha; Yuan, Pingfan; Wu, Huaxun; Chen, Jingyu; Fu, Jingjing; Li, Peipei; Lü, Jing-Tao; Wei, Wei

doi:10.1016/j.intimp.2014.02.027

Cited by 72 publications

(53 citation statements)

References 31 publications

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“…Several reports have shown that TGF‐β1 induces ZEB1 expression and EMT . Our data showed that TGF‐β1 induced ZEB1, and subsequently induced PD‐L1 expression in ESCC, which is consistent with several reports showing PD‐L1 induction by TGF‐β …”

Section: Discussionsupporting

confidence: 92%

“…(34,35) Our data showed that TGF-b1 induced ZEB1, and subsequently induced PD-L1 expression in ESCC, which is consistent with several reports showing PD-L1 induction by TGF-b. (55)(56)(57) In conclusion, PD-L1 expression at the invasive front was related to ZEB1 expression, EMT and poor prognosis in ESCC. We suggest that a cooperative mechanism between tumor immune avoidance and EMT contributes to tumor malignancy.…”

Section: Discussionmentioning

confidence: 81%

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Programmed death‐ligand 1 expression at tumor invasive front is associated with epithelial‐mesenchymal transition and poor prognosis in esophageal squamous cell carcinoma

et al. 2017

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Programmed death‐ligand 1 (PD‐L1) plays a crucial role in the host immune system in cancer progression. The gene promoter region of PD‐L1 also contains a binding site for ZEB1, a transcription factor related to epithelial‐mesenchymal transition (EMT). The purpose of this study was to clarify the relationship between PD‐L1 and EMT and its clinical importance in esophageal squamous cell carcinoma (ESCC). PD‐L1 and ZEB1 expression at the tumor invasive front was examined by immunohistochemistry in resected specimens from 90 patients with ESCC who underwent surgery without preoperative therapy, and their expression and clinicopathological factors were compared. ZEB1 and PD‐L1 expression was determined in TE8 cells, which demonstrate the EMT phenotype, following ZEB1 knockdown by siZEB1. TE5, TE6 and TE11 cells with non‐EMT phenotype were also used for studies of TGF‐β1‐dependent EMT induction and ZEB1 and PD‐L1 expression. In cases of high PD‐L1 expression at the invasive front, significantly greater depth of tumor invasion, EMT, and less CD8+ lymphocyte infiltration were observed. High PD‐L1 expression was also associated with worse overall and relapse‐free survival. A correlation was observed between PD‐L1 and ZEB1 expression. In TE8 cells, siZEB1 suppressed PD‐L1 and promoted E‐cadherin mRNA and protein expression. TGF‐β1 induced EMT and surface expression of PD‐L1 in TE5, TE6 and TE11 cell lines. PD‐L1 expression at the ESCC invasive front was related to ZEB1 expression, EMT and poor prognosis. We suggest that a cooperative mechanism bridging between tumor immune avoidance and EMT contributes to tumor malignancy in ESCC.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 81%

Programmed death‐ligand 1 expression at tumor invasive front is associated with epithelial‐mesenchymal transition and poor prognosis in esophageal squamous cell carcinoma

et al. 2017

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“…Finally, TGF-b, a molecule that is in general considered an anti-inflammatory cytokine, appears to have a contextdependent effect on PD-L1 expression. Specifically, whereas exposure of cultured monocytes (Ou et al, 2012) or tubular epithelial cells (Starke et al, 2007) to TGF-b represses PD-L1 expression, production of TGF-b by CD8 T cells in an in vivo model of pancreatic islet transplantation was shown to be required for sustained expression of PD-L1 by the same cells (Baas et al, 2016), in line with the observation that TGF-b induces PD-L1 expression in dendritic cells in vitro (Ni et al, 2012;Song et al, 2014). Similarly, IL-12-mediated PD-L1 regulation is also context dependent, as it positively regulates PD-L1 in endothelial cells and monocyte-derived macrophages but represses its expression in macrophages derived from the monocytic cell line THP-1 (Xiong et al, 2014).…”

Section: Control Of Pd-l1 Gene Expression Through Inflammatory Signalingmentioning

confidence: 62%

Regulation and Function of the PD-L1 Checkpoint

2018

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Expression of programmed death-ligand 1 (PD-L1) is frequently observed in human cancers. Binding of PD-L1 to its receptor PD-1 on activated T cells inhibits anti-tumor immunity by counteracting T cell-activating signals. Antibody-based PD-1-PD-L1 inhibitors can induce durable tumor remissions in patients with diverse advanced cancers, and thus expression of PD-L1 on tumor cells and other cells in the tumor microenviroment is of major clinical relevance. Here we review the roles of the PD-1-PD-L1 axis in cancer, focusing on recent findings on the mechanisms that regulate PD-L1 expression at the transcriptional, posttranscriptional, and protein level. We place this knowledge in the context of observations in the clinic and discuss how it may inform the design of more precise and effective cancer immune checkpoint therapies.

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“…This is presumably secondary to a reduction of TGF-β by anti-LAP (Fig. 2B), since both genes could be up-regulated by TGF-β (17, 18). Thus, anti-LAP increased dendritic cells with a pro-inflammatory phenotype and decreased DCs with an anti-inflammatory phenotype in the spleen.…”

Section: Resultsmentioning

confidence: 99%

Targeting latency-associated peptide promotes antitumor immunity

et al. 2017

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Regulatory T cells promote cancer by suppressing anti-tumor immune responses. We found that anti-LAP antibody which targets the latency-associated peptide (LAP)/TGF-β complex on Tregs and other cells enhances anti-tumor immune responses and reduces tumor growth in models of melanoma, colorectal carcinoma and glioblastoma. Anti-LAP decreases LAP+ Tregs, tolerogenic dendritic cells and TGF-β secretion, and is associated with CD8+ T cell activation. Anti-LAP increases infiltration of tumors by cytotoxic CD8+ T cells and reduces CD103+ CD8 T cells in dLNs and spleen. We identified a role for CD103+ CD8 T cells in cancer. Tumor-associated CD103+ CD8 T cells have a tolerogenic phenotype with increased expression of CTLA-4 and IL-10 and decreased expression of IFN-γ, TNF-α, and granzymes. Adoptive transfer of CD103+ CD8 T cells promotes tumor growth whereas CD103 blockade limits tumorigenesis. Thus, anti-LAP targets multiple immunoregulatory pathways and represents a potential approach for cancer immunotherapy.

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Dendritic cells with an increased PD-L1 by TGF-β induce T cell anergy for the cytotoxicity of hepatocellular carcinoma cells

Cited by 72 publications

References 31 publications

Programmed death‐ligand 1 expression at tumor invasive front is associated with epithelial‐mesenchymal transition and poor prognosis in esophageal squamous cell carcinoma

Programmed death‐ligand 1 expression at tumor invasive front is associated with epithelial‐mesenchymal transition and poor prognosis in esophageal squamous cell carcinoma

Regulation and Function of the PD-L1 Checkpoint

Targeting latency-associated peptide promotes antitumor immunity

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