Department of General Thoracic Surgery, Osaka University Graduate School of Medicine, Osaka 565-0897, Japan.
Oncol Rep. 2017 Oct;38(4):2277-2284. doi: 10.3892/or.2017.5894. Epub 2017 Aug 9.
In cancer immunology, the programmed cell death 1-programmed cell death 1/ligand 1 (PD-1/PD-L1) pathway plays a major role. Anti-PD-1 and anti-PD-L1 antibodies provide reliable immunotherapy when given as treatment for various types of malignancy including lung cancer. PD-L1 expression in cancer cells has been reported to be a predictive factor for the therapeutic effects of immunotherapy. However, the mechanism of PD-L1 expression remains unclear. Another key process in cancer progression is epithelial-mesenchymal transition (EMT). In the present study, we investigated the mechanism of PD-L1 expression as well as changes in its expression during the EMT process in non-small cell lung cancer (NSCLC). In this study, A549 cells underwent EMT by treatment with TGF-β or chemotherapeutic agents and then PD-L1 expression was evaluated. The alterations of PD-L1 expression was also examined during the reverse EMT process; mesenchymal-epithelial transition (MET). The relationship between for PD-L1 expression and EMT status in clinical specimens with NSCLC after induction chemotherapy were analyzed by immunohistochemical staining. We found that PD-L1 expression was upregulated following TGF-β induction; in contrast, it was downregulated by TGF-β receptor-kinase inhibitors and the MET process. Furthermore, chemo-treatment increased TGF-β expression and enhances PD-L1 expression via autocrine TGF-β induced EMT. Analysis of clinical samples revealed a significant relationship between PD-L1 expression and EMT status (P<0.05). In conclusion, our results suggest that PD-L1 expression is regulated by TGF-β induced EMT and enhanced by chemo-treatment via the chemo-induced TGF-β signaling. The anti-PD-1/PD-L1 blockade may provide more effective anticancer activities in combination with chemotherapy in NSCLC.
在癌症免疫学中，程序性细胞死亡 1-程序性细胞死亡 1 配体 1（PD-1/PD-L1）通路起着重要作用。抗 PD-1 和抗 PD-L1 抗体在治疗各种类型的恶性肿瘤（包括肺癌）时作为治疗方法提供了可靠的免疫治疗。已经报道癌细胞中的 PD-L1 表达是免疫治疗疗效的预测因素。然而，PD-L1 表达的机制仍不清楚。癌症进展的另一个关键过程是上皮-间充质转化（EMT）。在本研究中，我们研究了非小细胞肺癌（NSCLC）中 EMT 过程中 PD-L1 表达及其表达变化的机制。在这项研究中，通过用 TGF-β或化疗药物处理 A549 细胞使其发生 EMT，然后评估 PD-L1 表达。还检查了 EMT 过程（间充质上皮转化（MET））中 PD-L1 表达的变化。通过免疫组织化学染色分析了 NSCLC 诱导化疗后临床标本中 PD-L1 表达与 EMT 状态之间的关系。我们发现 PD-L1 表达在 TGF-β诱导后上调；相反，它被 TGF-β 受体激酶抑制剂和 MET 过程下调。此外，化疗治疗通过自分泌 TGF-β诱导的 EMT 增加 TGF-β 表达并增强 PD-L1 表达。对临床样本的分析表明，PD-L1 表达与 EMT 状态之间存在显著关系（P<0.05）。总之，我们的结果表明，PD-L1 表达受 TGF-β 诱导的 EMT 调节，并通过化疗诱导的 TGF-β 信号增强化疗治疗。抗 PD-1/PD-L1 阻断可能与 NSCLC 中的化疗联合提供更有效的抗癌活性。
