PD-L1 induced by IFN-γ from tumor-associated macrophages via the JAK/STAT3 and PI3K/AKT signaling pathways promoted progression of lung cancer

Zhang, Xiaohui; Zeng, Yuanyuan; Qu, Qiuxia; Zhu, Jianjie; Liu, Zeyi; Ning, Weiwei; Zeng, Hui; Zhang, Nan; Du, Wenwen; Chen, Cheng; Huang, Jian-An

doi:10.1007/s10147-017-1161-7

Cited by 234 publications

(144 citation statements)

References 37 publications

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“…46–49 We assessed induction of STAT1/3/5 phosphorylation in MSP-treated macrophages in the presence of MEK1/2 or JAK inhibitors. Upon MSP stimulation, we detected higher levels of STAT1 serine-727 phosphorylation, a residue known to be a direct target of MAPK signaling, 50 (Figure 2d).…”

Section: Resultsmentioning

confidence: 99%

Inhibition of RON kinase potentiates anti-CTLA-4 immunotherapy to shrink breast tumors and prevent metastatic outgrowth

et al. 2018

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The advent of immune checkpoint blockade as a new strategy for immunotherapy has changed the outlook for many aggressive cancers. Although complete tumor eradication is attainable in some cases, durable clinical responses are observed only in a small fraction of patients, underlining urgent need for improvement. We previously showed that RON, a receptor tyrosine kinase expressed in macrophages, suppresses antitumor immune responses, and facilitates progression and metastasis of breast cancer. Here, we investigated the molecular changes that occur downstream of RON activation in macrophages, and whether inhibition of RON can cooperate with checkpoint immunotherapy to eradicate tumors. Activation of RON by its ligand, MSP, altered the gene expression profile of macrophages drastically and upregulated surface levels of CD80 and PD-L1, ligands for T-cell checkpoint receptors CTLA-4 and PD-1. Genetic deletion or pharmacological inhibition of RON in combination with anti-CTLA-4, but not with anti-PD-1, resulted in improved clinical responses against orthotopically transplanted tumors compared to single-agent treatment groups, resulting in complete tumor eradication in 46% of the animals. Positive responses to therapy were associated with higher levels of T-cell activation markers and tumor-infiltrating lymphocytes. Importantly, co-inhibition of RON and anti-CTLA-4 was also effective in clearing metastatic breast cancer cells in lungs, resulting in clinical responses in nearly 60% of the mice. These findings suggest that RON inhibition can be a novel approach to potentiate responses to checkpoint immunotherapy in breast cancer.

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Section: Resultsmentioning

confidence: 99%

Inhibition of RON kinase potentiates anti-CTLA-4 immunotherapy to shrink breast tumors and prevent metastatic outgrowth

et al. 2018

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“…NK cells and macrophage in nude mice 32 might infiltrate into the xenograft tumors, causing up-regulation of IL-6 and PD-L1 in tumor microenvironment. 33,34 The expression of IL-6/STAT3 and PD-L1 of the HNSCC xenografts and its immunological mechanism after LfcinB injection is worthwhile for investigation in the further studies.…”

Section: Discussionmentioning

confidence: 99%

Lactoferricin B reverses cisplatin resistance in head and neck squamous cell carcinoma cells through targeting PD‐L1

Zhang

Liu

et al. 2018

Cancer Medicine

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Head and neck squamous cell carcinoma (HNSCC) ranks among the top most common cancers with a poor prognosis. The mechanism of chemoresistance is still not well known. This study is to investigate the programmed death‐ligand 1 (PD‐L1) expression in HNSCC, and test the effect of lactoferricin B (LfcinB) on chemoresistance and its mechanism. We analyzed 510 HNSCC patients in TCGA database and investigated how CD274 expression was related to patient prognosis. PD‐L1 was verified from HNSCC samples at local hospital with immunohistochemistry. PD‐L1 expression in the acquired cisplatin‐resistant HNSCC cells was examined by PCR and WB in order to test PD‐L1‐induced chemoresistance. LfcinB inoculation in cisplatin‐resistant HNSCC cells and in the nude mice was introduced to test the effect of LfcinB on targeting cisplatin resistance and its mechanism. High CD274 mRNA (>125 FPKM) from TCGA database had a significantly reduced 5‐year survival rate, and a lower 5‐year survival rate in the chemotherapy and radiotherapy‐treated patients (P < .05). PD‐L1 overexpression was further supported from analysis of 40 HNSCC specimens. PD‐L1 and IL‐6 in the established cisplatin‐resistant HNSCC cells were shown significantly higher (P < .05). IL‐6 and PD‐L1 expression were partially inhibited by the anti‐IL‐6/STAT3 antibody. LfcinB displayed a direct cytotoxic effect on cisplatin‐resistant HNSCC cells and HNSCC xenografts of cisplatin‐resistant cells in the nude mice displayed significant reduction in tumor volume after LfcinB injection (P < .05). Besides, the increase of IL‐6 and PD‐L1 in cisplatin‐resistant HNSCC cells was abolished in vitro by LfcinB (P < .05). PD‐L1 expression in HNSCC cells correlates with poor prognosis and chemoresistance, and LfcinB might provide therapeutic potential in HNSCC patients through modulating IL‐6 and PD‐L1.

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“…Cytotoxic T lymphocytes (CTL) are stimulated by IFNγ production after the TCR binds the MHC, and IFNγ promotes PD-L1 expression in cancer cells via the JAK/STAT pathway. 38,39 The transcription factor NF-κB, which is downstream of TNFα, has been shown to induce the expression of inflammatory mediators and other transcription factors during the immune response, suggesting that NF-κB is responsible for both inflammation-induced carcinogenesis and anti-tumor immunity. To address the molecular mechanism of PD-L1 expression, we examined the effect of an NF-κB inhibitor on PD-L1 expression and showed that NF-κB signaling was important in PD-L1 upregulation in PDAC cells.…”

Section: In General Naive T Cells Accumulate Around Cancer Cells Andmentioning

confidence: 99%

PD‐L1 expression enhancement by infiltrating macrophage‐derived tumor necrosis factor‐α leads to poor pancreatic cancer prognosis

et al. 2018

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Immunotherapy using anti‐PD‐1/PD‐L1 antibodies for several types of cancer has received considerable attention in recent decades. However, the molecular mechanism underlying PD‐L1 expression in pancreatic ductal adenocarcinoma (PDAC) cells has not been clearly elucidated. We investigated the clinical significance and regulatory mechanism of PD‐L1 expression in PDAC cells. Among the various cytokines tested, tumor necrosis factor (TNF)‐α upregulated PD‐L1 expression in PDAC cells through NF‐κB signaling. The induction of PD‐L1 expression was also caused by co‐culture with activated macrophages, and the upregulation was inhibited by neutralization with anti‐TNF‐α antibody after co‐culture with activated macrophages. PD‐L1 expression in PDAC cells was positively correlated with macrophage infiltration in tumor stroma of human PDAC tissues. In addition, survival analysis revealed that high PD‐L1 expression was significantly associated with poor prognosis in 235 PDAC patients and especially in patients harboring high CD8‐positive T‐cell infiltration. These findings indicate that tumor‐infiltrating macrophage‐derived TNF‐α could be a potential therapeutic target for PDAC.

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PD-L1 induced by IFN-γ from tumor-associated macrophages via the JAK/STAT3 and PI3K/AKT signaling pathways promoted progression of lung cancer

Abstract: IFN-γ was not always successful as an antitumor agent. It also can promote tumor cells to evade immune surveillance. Researchers should be cautious in using IFN-γ as a therapeutic agent for cancer treatment.

Cited by 234 publications

References 37 publications

Inhibition of RON kinase potentiates anti-CTLA-4 immunotherapy to shrink breast tumors and prevent metastatic outgrowth

Inhibition of RON kinase potentiates anti-CTLA-4 immunotherapy to shrink breast tumors and prevent metastatic outgrowth

Lactoferricin B reverses cisplatin resistance in head and neck squamous cell carcinoma cells through targeting PD‐L1

PD‐L1 expression enhancement by infiltrating macrophage‐derived tumor necrosis factor‐α leads to poor pancreatic cancer prognosis

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