Department of Respiratory Medicine, The First Affiliated Hospital of Soochow University, Suzhou, 215123, People's Republic of China.
Institute of Respiratory Diseases, Soochow University, Suzhou, People's Republic of China.
Int J Clin Oncol. 2017 Dec;22(6):1026-1033. doi: 10.1007/s10147-017-1161-7. Epub 2017 Jul 26.
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.
背景：干扰素-γ（IFN-γ）通常被认为是一种炎症细胞因子，在抗感染和肿瘤免疫监视中起着关键作用。它已在临床上用于治疗多种恶性肿瘤。然而，越来越多的证据表明 IFN-γ 可诱导肿瘤进展。IFN-γ 在调节抗肿瘤免疫中的作用似乎是复杂和矛盾的。IFN-γ 在抗肿瘤免疫中的双重作用的机制尚不清楚。
方法：（1）用胸腔积液或肿瘤相关巨噬细胞（TAM）上清液培养肺癌细胞（A549 细胞），用流式细胞仪检测 PD-L1 的表达水平。用 Trans-well 迁移实验体外测定侵袭能力。（2）用 Ficoll Hypaque 梯度分离胸腔积液单核细胞（PEMC）。用流式细胞术分析肿瘤相关巨噬细胞中白细胞介素（IL）-6、IL-10、肿瘤坏死因子（TNF）-α和 INF-γ的表达。（3）用 IL-6、IL-10、TNF-α或 IFN-γ刺激 A549 细胞，然后用流式细胞术检测其表达水平。（4）用 Western blot 分析 IFN-γ刺激后磷酸化 ERK（p-ERK）、磷酸化 AKT（p-AKT）和磷酸化 Sat3（p-Stat3）的表达水平。（5）用 MAPK/ERK 特异性抑制剂 PD98059、PI3K/AKT 特异性抑制剂 LY294002 或 JAK/STAT3 特异性抑制剂 AG490 分别处理 A549 细胞，阻断 IFN-γ诱导的 PD-L1 表达，然后用流式细胞术检测 PD-L1 表达。
结果：我们证明 TAMs 通过 Janus 激酶/信号转导和转录激活子 3（JAK/STAT3）信号通路和磷脂酰肌醇 3-激酶（PI3K）/AKT 信号通路分泌 IFN-γ诱导 A549 细胞中 PD-L1 的表达。此外，信号通路阻断剂 LY294002 或 AG490 可阻断 IFN-γ诱导的 PD-L1 表达。
结论：IFN-γ 作为抗肿瘤药物并不总是成功的。它还可以促进肿瘤细胞逃避免疫监视。研究人员在将 IFN-γ 用作癌症治疗的治疗剂时应谨慎。
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