STAT3 Induces Immunosuppression by Upregulating PD-1/PD-L1 in HNSCC

Bu, Lin‐Lin; Yu, Guang‐Tao; Wu, Lei; Mao, Liang; Deng, Wei‐Wei; Liu, J.F.; Kulkarni, Ashok B.; Zhang, W.F.; Zhang, L.; Sun, Zhi‐Jun

doi:10.1177/0022034517712435

Cited by 157 publications

(124 citation statements)

References 37 publications

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“…Because we observed that EGF induced IRF‐1 (Figures D and E), we ascertained that EGFR induced not only STAT1 but also IRF‐1 expression to increase the PD‐L1 level in selected EGFR‐positive cancers. EGFR can phosphorylate STAT3, which has been reported to determine the expression of PD‐L1; therefore, we speculated that EGFR‐STAT3 mediated the expression of STAT1 and IRF‐1 that was evaluated in this study (Figure G).…”

Section: Discussionmentioning

confidence: 82%

“…These findings indicate that phosphorylated STAT1 was derived from the IFNr‐JAK1/JAK2 signaling axis to determine PD‐L1 expression, whereas EGF exacerbated PD‐L1 expression by increasing the protein levels of STAT1. Since EGFR‐STAT3 has been documented participating in cancer stemness and inducing PD‐L1 expression, we then knockdowned and inhibited STAT3 in A549 cells by shRNA technique and BBI608, a STAT3 inhibitor, respectively. We found decreased expression of STAT1, IRF‐1, and PD‐L1 in A549shSTAT3 cells compared to that in A549shLuc cells (Figure G).…”

Section: Resultsmentioning

confidence: 99%

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Epidermal growth factor induces STAT1 expression to exacerbate the IFNr‐mediated PD‐L1 axis in epidermal growth factor receptor‐positive cancers

Cheng¹,

Lin

Tsai³

et al. 2018

Molecular Carcinogenesis

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The epidermal growth factor (EGF) receptor (EGFR) overexpressed in many cancers, including lung and head and neck cancers, and is involved in cancer cell progression and survival. PD-L1, increases in tumor cells to evade and inhibit CD8+ T cells, is a clinical immunotherapeutic target. This study investigated the molecular mechanism of EGF on regulating PD-L1 in EGFR-positive cancers and determined potential agents to reduce PD-L1 expression. RNA sequencing (RNAseq) and bioinformatics analysis were performed to determine potential driver genes that regulate PD-L1 in tumor cells-derived tumorspheres which mimicking cancer stem cells. Then, the specific inhibitors targeting EGFR were applied to reduce the expression of PD-L1 in vitro and in vivo. We validated that EGF could induce PD-L1 expression in the selected EGFR-positive cancers. RNAseq results revealed that STAT1 increased as a driver gene in KOSC-3-derived tumorspheres; these data were analyzed using PANTHER followed by NetworkAnalyst. The blockade of EGFR by afatinib resulted in decreased STAT1 and IRF-1 levels, both are transcriptional factors of PD-L1, and disabled the IFNr-STAT1-mediated PD-L1 axis in vitro and in vivo. Moreover, STAT1 knockdown significantly reduced EGF-mediated PD-L1 expression, and ruxolitinib, a JAK1/JAK2 inhibitor, significantly inhibited STAT1 phosphorylation to reduce the IFNr-mediated PD-L1 axis. These results indicate that EGF exacerbates PD-L1 by increasing the protein levels of STAT1 to enforce the IFNr-JAK1/2-mediated signaling axis in selected EGFR-positive cancers. The inhibition of EGFR by afatinib significantly reduced PD-L1 and may be a potential strategy for enhancing immunotherapeutic efficacy.

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Section: Discussionmentioning

confidence: 82%

Section: Resultsmentioning

confidence: 99%

Epidermal growth factor induces STAT1 expression to exacerbate the IFNr‐mediated PD‐L1 axis in epidermal growth factor receptor‐positive cancers

Cheng¹,

Lin

Tsai³

et al. 2018

Molecular Carcinogenesis

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“…[ lymphoma (Marzec et al, 2008;Atsaves et al, 2017), melanoma (Jiang et al, 2013), HNSCC (Bu et al, 2017) RELA [ primary monocytes (Huang et al, 2013), melanoma (Gowrishankar et al, 2015), NSCLC (Bouillez et al, 2017), breast cancer (Xue et al, 2017) MUC1-C [ NSCLC (Bouillez et al, 2017) JUN [ lymphoma (Green et al, 2012), melanoma (Jiang et al, 2013) CDK5…”

Section: Stat3mentioning

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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“…It has been shown that increased JAK2 upregulates STAT1 but not STAT3 in HNSCC cell lines, resulting in increased PD‐L1 (Concha‐Benavente et al, ). Another study in a different HNSCC cell line (CAL27) found that blockade of STAT3 produced the loss of PD‐L1 overexpression (Bu et al, ). These contrasting results illustrate the importance of different JAK/STAT pathways in distinct HNSCC cell lines.…”

Section: Pd‐l1 In Cancermentioning

confidence: 99%

An update of knowledge on PD‐L1 in head and neck cancers: Physiologic, prognostic and therapeutic perspectives

et al. 2019

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Programmed cell death‐ligand 1 (PD‐L1) is a transmembrane protein that acts as a co‐inhibitory factor in the immune response. Its receptor, programmed cell death protein 1 (PD‐1), is found on immune cells, where binding to PD‐L1 can reduce the proliferation of PD‐1‐positive cells, inhibit their cytokine secretion and induce apoptosis. PD‐L1 in immune‐privileged tissue plays a crucial role in peripheral tolerance. PD‐L1 can be overexpressed in various malignancies, including oral squamous cell carcinoma, where it can attenuate the host immune response to tumour cells and has been associated with a worse prognosis. Monoclonal antibody therapies targeting the PD‐1:PD‐L1 axis have shown initial promise, but further research is needed to identify which patients will benefit. We provide an update of knowledge on PD‐L1, including its structure, function and regulation. We also review studies on the overexpression of PD‐L1 in cancer, specifically oral squamous cell carcinoma, and explore its potential value as a therapeutic target.

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STAT3 Induces Immunosuppression by Upregulating PD-1/PD-L1 in HNSCC

Cited by 157 publications

References 37 publications

Epidermal growth factor induces STAT1 expression to exacerbate the IFNr‐mediated PD‐L1 axis in epidermal growth factor receptor‐positive cancers

Epidermal growth factor induces STAT1 expression to exacerbate the IFNr‐mediated PD‐L1 axis in epidermal growth factor receptor‐positive cancers

Regulation and Function of the PD-L1 Checkpoint

An update of knowledge on PD‐L1 in head and neck cancers: Physiologic, prognostic and therapeutic perspectives

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