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The TLR4/ERK/PD?L1 axis may contribute to NSCLC initiation.

ABSTRACT: Infection and inflammation serve an important role in tumor development. Toll?like receptor 4 (TLR4) is a pivotal component of the innate and adaptive immune response during infection and inflammation. Programmed?death ligand 1 (PD?L1) is hypothesized as an important factor for non?small cell lung cancer (NSCLC) immune escape. In the present study, the relationship between TLR4 and PD?L1, in addition to the associated molecular mechanism, were investigated. TLR4 and PD?L1 expression in lung cancer tissues were detected using immunohistochemistry, whilst overall patient survival was measured using the Kaplan?Meier method. The A549 cell line stimulated using lipopolysaccharide (LPS) was applied as the in vitro inflammatory NSCLC model. Associated factors were investigated using reverse transcription?quantitative PCR and western blotting. Lung cancer tissues exhibited increased PD?L1 and TLR4 levels compared with those of adjacent para?cancerous tissues, where there was a positive correlation between TLR4 and PD?L1 expression. In addition, increased expression of these two proteins was found to be linked with poorer prognoses. Following the stimulation of A549 cells with LPS, TLR4 and PD?L1 expression levels were revealed to be upregulated in a dose?dependent manner, where the ERK and PI3K/AKT signaling pathways were found to be activated. Interestingly, in the presence of inhibitors of these two pathways aforementioned, upregulation of PD?L1 expression was only inhibited by the MEK inhibitor PD98059, which can inhibit ERK activity. These data suggested that the ERK signaling pathway is necessary for the TLR4/PD?L1 axis. In conclusion, data from the present study suggest that TLR4 and PD?L1 expression can serve as important prognostic factors for NSCLC, where TLR4 activation may induce PD?L1 expression through the ERK signaling pathway.

SUBMITTER: Kang X

PROVIDER: S-EPMC7307593 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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The TLR4/ERK/PD‑L1 axis may contribute to NSCLC initiation.

Kang Xiuhua X Li Penghui P Zhang Chuibin C Zhao Yunshan Y Hu Huoli H Wen Guilan G

International journal of oncology 20200519 2

Infection and inflammation serve an important role in tumor development. Toll‑like receptor 4 (TLR4) is a pivotal component of the innate and adaptive immune response during infection and inflammation. Programmed‑death ligand 1 (PD‑L1) is hypothesized as an important factor for non‑small cell lung cancer (NSCLC) immune escape. In the present study, the relationship between TLR4 and PD‑L1, in addition to the associated molecular mechanism, were investigated. TLR4 and PD‑L1 expression in lung canc ...[more]

PMID: 32468028

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Project description:BACKGROUND:PD-L1 is an immune inhibitory receptor ligand that leads to T cell dysfunction and apoptosis by binding to its receptor PD-1, which works in braking inflammatory response and conspiring tumor immune evasion. However, in gliomas, the cause of PD-L1 expression in the tumor microenvironment is not yet clear. Besides, auxiliary biomarkers are urgently needed for screening possible responsive glioma patients for anti-PD-1/PD-L1 therapies. METHODS:The distribution of tumor-infiltrating T cells and PD-L1 expression was analyzed via immunofluorescence in orthotopic murine glioma model. The expression of PD-L1 in immune cell populations was detected by flow cytometry. Data excavated from TCGA LGG/GBM datasets and the Ivy Glioblastoma Atlas Project was used for in silico analysis of the correlation among genes and survival. RESULTS:The distribution of tumor-infiltrating T cells and PD-L1 expression, which parallels in murine orthotopic glioma model and human glioma microdissections, was interrelated. The IFN-? level was positively correlated with PD-L1 expression in murine glioma. Further, IFN-? induces PD-L1 expression on primary cultured microglia, bone marrow-derived macrophages, and GL261 glioma cells in vitro. Seven IFN-?-induced genes, namely GBP5, ICAM1, CAMK2D, IRF1, SOCS3, CD44, and CCL2, were selected to calculate as substitute indicator for IFN-? level. By combining the relative expression of the listed IFN-?-induced genes, IFN-? score was positively correlated with PD-L1 expression in different anatomic structures of human glioma and in glioma of different malignancies. CONCLUSION:Our study identified the distribution of tumor-infiltrating T cells and PD-L1 expression in murine glioma model and human glioma samples. And we found that IFN-? is an important cause of PD-L1 expression in the glioma microenvironment. Further, we proposed IFN-? score aggregated from the expressions of the listed IFN-?-induced genes as a complementary prognostic indicator for anti-PD-1/PD-L1 therapy.

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The TLR4/ERK/PD?L1 axis may contribute to NSCLC initiation.

Publications

The TLR4/ERK/PD‑L1 axis may contribute to NSCLC initiation.

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