IL-12 Regulates B7-H1 Expression in Ovarian Cancer-associated Macrophages by Effects on NF-κB Signalling

Xiong, Hai-Yu; Ma, Tingting; Wu, Bitao; Tu, Zhiguang

doi:10.7314/apjcp.2014.15.14.5767

Cited by 28 publications

(23 citation statements)

References 37 publications

(37 reference statements)

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“…Together, these findings suggest that IL-17 and/or TNF-α act through activation of NF-κB and ERK1/2 signaling to up-regulate PD-L1 expression in HCT116 cells, while the two cytokines act through activation of NF-κB signaling, in the presence of AKT activity, to up-regulate PD-L1 expression in LNCaP cells. Our findings are consistent with several previous studies showing that NF-κB plays a key role in regulating PD-L1 expression [31–34]. Previous studies have also demonstrated that activation of ERK1/2 signaling drives PD-L1 expression in melanomas and lung cancers [35,36].…”

Section: Discussionsupporting

confidence: 93%

Inflammatory cytokines IL-17 and TNF-α up-regulate PD-L1 expression in human prostate and colon cancer cells

et al. 2017

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Programmed cell death protein 1 (PD-1) acts on PD-1 ligands (PD-L1 and PD-L2) to suppress activation of cytotoxic T lymphocytes. Interleukin-17 (IL-17) and tumor necrosis factor-α (TNF-α) are co-expressed by T helper 17 (TH17) cells in many tumors. The purpose of this study was to test if IL-17 and TNF-α may synergistically induce PD-L1 expression in human prostate cancer LNCaP and human colon cancer HCT116 cell lines. We found that IL-17 did not induce PD-L1 mRNA expression, but up-regulated PD-L1 protein expression in HCT116 and LNCaP cells. TNF-α induced PD-L1 mRNA and protein expression in both cell lines. Neither IL-17 nor TNF-α induced PD-L2 mRNA or protein expression. IL-17 and TNF-α acted individually rather than cooperatively in induction of PD-L1 expression. IL-17 and/or TNF-α activated AKT, nuclear factor-κB (NF-κB), and extracellular signal-regulated kinases 1/2 (ERK1/2) signaling pathways in HCT116 cells, whereas only NF-κB signaling was activated in LNCaP cells. NF-κB inhibitor could diminish PD-L1 protein expression induced by IL-17 and/or TNF-α in both HCT116 and LNCaP cell lines. ERK1/2 inhibitor could also reduce PD-L1 protein expression induced by IL-17 and/or TNF-α in HCT116 cells, while AKT inhibitor could abolish PD-L1 protein expression induced by IL-17 and/or TNF-α in LNCaP cells. These results suggest that IL-17 and TNF-α act individually rather than cooperatively through activation of NF-κB and ERK1/2 signaling to up-regulate PD-L1 expression in HCT116 cells, while the two inflammatory cytokines act through activation of NF-κB signaling, in the presence of AKT activity, to up-regulate PD-L1 expression in LNCaP cells.

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Section: Discussionsupporting

confidence: 93%

Inflammatory cytokines IL-17 and TNF-α up-regulate PD-L1 expression in human prostate and colon cancer cells

et al. 2017

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“…32 As an important transcription factor, NF-κB transactivates PD-L1 expression by binding directly to the PD-L1 promoter. 33 Further flow cytometry analysis indicated that NSCLC cells with mutated EGFR showed clearly higher percentages of cells that were both EGFR and PD-L1 positive on the cell surface than the remaining NSCLC cell lines carrying WT EGFR. Another important transcription factor, HIF-1α, increases the expression of PD-L1 in hypoxic cancer cells by binding directly to the hypoxia response element in the PD-L1 promoter.…”

Section: Discussionmentioning

confidence: 94%

“…Activated AKT, as a key downstream effector of the EGFR pathway, has been reported to activate NF‐κB and thereby regulate PD‐L1 expression . As an important transcription factor, NF‐κB transactivates PD‐L1 expression by binding directly to the PD‐L1 promoter . NF‐κB is bound and inhibited by IκBs in the cytoplasm of unstimulated cells.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia‐inducible factor‐1α and nuclear factor‐κB play important roles in regulating programmed cell death ligand 1 expression by epidermal growth factor receptor mutants in non‐small‐cell lung cancer cells

Guo

Wang

et al. 2019

Cancer Science

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Some driver gene mutations, including epidermal growth factor receptor ( EGFR ), have been reported to be involved in expression regulation of the immunosuppressive checkpoint protein programmed cell death ligand 1 ( PD ‐L1), but the underlying mechanism remains obscure. We investigated the potential role and precise mechanism of EGFR mutants in PD ‐L1 expression regulation in non‐small‐cell lung cancer ( NSCLC ) cells. Examination of pivotal EGFR signaling effectors in 8 NSCLC cell lines indicated apparent associations between PD ‐L1 overexpression and phosphorylation of AKT and ERK , especially with increased protein levels of phospho‐IκBα (p‐IκBα) and hypoxia‐inducible factor‐1α (HIF‐1α). Flow cytometry results showed stronger membrane co‐expression of EGFR and PD ‐L1 in NSCLC cells with EGFR mutants compared with cells carrying WT EGFR . Additionally, ectopic expression or depletion of EGFR mutants and treatment with EGFR pathway inhibitors targeting MEK / ERK , PI 3K/ AKT , mTOR /S6, IκBα, and HIF ‐1α indicated strong accordance among protein levels of PD ‐L1, p‐IκBα, and HIF ‐1α in NSCLC cells. Further treatment with pathway inhibitors significantly inhibited xenograft tumor growth and p‐IκBα, HIF ‐1α, and PD ‐L1 expression of NSCLC cells carrying EGFR mutant in nude mice. Moreover, immunohistochemical analysis revealed obviously increased protein levels of p‐IκBα, HIF ‐1α, and PD ‐L1 in NSCLC tissues with EGFR mutants compared with tissues carrying WT EGFR . Non‐small‐cell lung cancer tissues with either p‐IκBα or HIF ‐1α positive staining were more likely to possess elevated PD ‐L1 expression compared with tissues scored negative for both p‐IκBα and HIF ‐1α. Our findings showed important roles of phosphorylation activation of AKT and ERK and potential interplay and cooperation between NF ‐κB and HIF ‐1α in PD ‐L1 expression regulation by EGFR mutants in NSCLC .

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“…[ dendritic cells (Pulko et al, 2009), endothelial cells (Cole et al, 2011), neuroblastoma (Boes and Meyer-Wentrup, 2015) IL-17 [ monocytes (Zhao et al, 2011), prostate and colon cancer (Wang et al, 2017b) IL-10 [ dendritic cells (Curiel et al, 2003), monocytes (Zhao et al, 2011) TNF-a [ endothelial cells (Mazanet and Hughes, 2002), myelodysplastic syndrome blasts (Kondo et al, 2010), dendritic cells (Karakhanova et al, 2010), monocytes (Zhao et al, 2011), monocytes (Ou et al, 2012), RCC (Quandt et al, 2014), breast cancer (Lim et al, 2016), prostate and colon cancer (Wang et al, 2017b) IL-4 [ RCC (Quandt et al, 2014) IL-1b [ dendritic cells (Karakhanova et al, 2010) IL-6 [ dendritic cells (Karakhanova et al, 2010;Kil et al, 2017) IL-27 [ dendritic cells (Karakhanova et al, 2011;Matta et al, 2012), ovarian cancer (Carbotti et al, 2015) TGF-b [ dendritic cells (Ni et al, 2012;Song et al, 2014), T cells (Baas et al, 2016) Y renal tubular epithelial cells (Starke et al, 2007), monocytes (Ou et al, 2012) IL-12 [ endothelial cells (Eppihimer et al, 2002), monocyte-derived macrophages (Xiong et al, 2014) Y THP-1-derived macrophages (Xiong et al, 2014) Oncogenic signaling…”

Section: Tlr4mentioning

confidence: 99%

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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IL-12 Regulates B7-H1 Expression in Ovarian Cancer-associated Macrophages by Effects on NF-κB Signalling

Cited by 28 publications

References 37 publications

Inflammatory cytokines IL-17 and TNF-α up-regulate PD-L1 expression in human prostate and colon cancer cells

Inflammatory cytokines IL-17 and TNF-α up-regulate PD-L1 expression in human prostate and colon cancer cells

Hypoxia‐inducible factor‐1α and nuclear factor‐κB play important roles in regulating programmed cell death ligand 1 expression by epidermal growth factor receptor mutants in non‐small‐cell lung cancer cells

Regulation and Function of the PD-L1 Checkpoint

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