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

• Published in: International journal of clinical oncology 2017-12, Vol.22 (6), p.1026-1033
• Main Authors: Zhang, Xiaohui, Zeng, Yuanyuan, Qu, Qiuxia, Zhu, Jianjie, Liu, Zeyi, Ning, Weiwei, Zeng, Hui, Zhang, Nan, Du, Wenwen, Chen, Cheng, Huang, Jian-an
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; AKT protein; B7-H1 Antigen - metabolism; Cancer Research; Cell Line, Tumor; Cells; Extracellular signal-regulated kinase; Flavonoids; Flow cytometry; Humans; Immune system; Immunosurveillance; Inflammation; Interferon; Interferon-gamma - metabolism; Interferon-gamma - pharmacology; Interleukin 10; Interleukin 6; Interleukin-10 - metabolism; Interleukin-6 - metabolism; Janus kinase; Janus Kinases - metabolism; Leukocyte migration; Leukocytes (mononuclear); Lung cancer; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Macrophages; Macrophages - drug effects; Macrophages - metabolism; Macrophages - pathology; MAP kinase; Medicine; Medicine & Public Health; Oncology; Original Article; PD-L1 protein; Phosphatidylinositol 3-Kinases - metabolism; Pleural effusion; Protein Kinase Inhibitors - pharmacology; Proto-Oncogene Proteins c-akt - metabolism; Signal transduction; Signal Transduction - drug effects; Stat3 protein; STAT3 Transcription Factor - metabolism; Surgical Oncology; Transcription; Tumor cells; Tumor Necrosis Factor-alpha - metabolism; Tumor necrosis factor-TNF; Tyrphostins - pharmacology; γ-Interferon
• ISSN: 1341-9625; 1437-7772
• DOI: 10.1007/s10147-017-1161-7

Background Interferon-γ (IFN-γ) is conventionally regarded as an inflammatory cytokine that has a pivotal role in anti-infection and tumor immune surveillance. It has been used clinically to treat a variety of malignancies. However, increased evidence has suggested IFN-γ can act to induce tumor progression. The role of IFN-γ in regulating antitumor immunity appears to be complex and paradoxical. The mechanism underlying the dual aspects of IFN-γ function in antitumor immunity is not clear. Methods (1) Lung cancer cells (A549 cells) were cultured with pleural effusion or supernatant of tumor-associated macrophages (TAMs supernatant), and the expression levels of PD-L1 were detected by flow cytometer. The invasion capacity was measured in vitro using trans-well migration assays. (2) Pleural effusion mononuclear cells (PEMC) were separated by Ficoll Hypaque gradient. The expression of interleukin (IL)-6, IL-10, tumor necrosis factor (TNF)-α, and INF-γ in the tumor-associated macrophages was analyzed by flow cytometry. (3) A549 cells were stimulated with IL-6, IL-10, TNF-α, or IFN-γ and then the expression levels were detected by flow cytometry. (4) The expression levels of phospho-ERK ( p -ERK), phospho-AKT ( p -AKT), and phospho-Sat3 ( p -Stat3) were analyzed with Western blot after stimulation with IFN-γ. (5) Cotreatment of the A549 cells with MAPK/ERK-specific inhibitor PD98059, PI3K/AKT-specific inhibitor LY294002, or JAK/STAT3-specific inhibitor AG490, respectively, blocked IFN-γ-induced PD-L1 expression, and then PD-L1 expression was detected by flow cytometry. Results We demonstrated that TAMs could induce the expression of PD-L1 by the secretion of IFN-γ through the Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) signaling pathway and the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway in A549 cells. Furthermore, the signal pathway blockers LY294002 or AG490 could block the induced expression of PD-L1 by IFN-γ. Conclusions 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.