期刊
INTERNATIONAL JOURNAL OF CLINICAL ONCOLOGY
卷 22, 期 6, 页码 1026-1033出版社
SPRINGER JAPAN KK
DOI: 10.1007/s10147-017-1161-7
关键词
Lung cancer; Tumor microenvironment; Tumor-associated macrophage; Cytokine; PD-L1; Signaling pathway
类别
资金
- National Natural Science Foundation of China [31270940]
- Clinical Medical Center of Suzhou [Szzx201502]
- Suzhou Key Laboratory for Respiratory Medicine [SZS201617]
- Societal and Developmental Project of Suzhou [SS201630]
- Foundation of Health Care Rejuvenation by Science and Education [KJXW2016003]
- Clinical Key Specialty Project of China
Background Interferon-gamma (IFN-gamma) 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-gamma can act to induce tumor progression. The role of IFN-gamma in regulating antitumor immunity appears to be complex and paradoxical. The mechanism underlying the dual aspects of IFN-gamma 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)-alpha, and INF-gamma in the tumor-associated macrophages was analyzed by flow cytometry. (3) A549 cells were stimulated with IL-6, IL-10, TNF-alpha, or IFN-gamma 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-gamma. (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-gamma-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-gamma 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-gamma. Conclusions IFN-gamma 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-gamma as a therapeutic agent for cancer treatment.
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