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Intrinsic and Extrinsic Regulation of PD-L2 Expression in Oncogene-Driven Non–Small Cell Lung Cancer
Journal of Thoracic Oncology ( IF 20.4 ) Pub Date : 2018-07-01 , DOI: 10.1016/j.jtho.2018.03.012
Daisuke Shibahara , Kentaro Tanaka , Eiji Iwama , Naoki Kubo , Keiichi Ota , Koichi Azuma , Taishi Harada , Jiro Fujita , Yoichi Nakanishi , Isamu Okamoto

Introduction: The interaction of programmed cell death ligand 2 (PD‐L2) with programmed cell death 1 is implicated in tumor immune escape. The regulation of PD‐L2 expression in tumor cells has remained unclear, however. We here examined intrinsic and extrinsic regulation of PD‐L2 expression in NSCLC. Methods: PD‐L2 expression was evaluated by reverse transcription and real‐time polymerase chain reaction analysis and by flow cytometry. Results: BEAS‐2B cells stably expressing an activated mutant form of EGFR or the echinoderm microtubule associated protein like 4 (EML4)–ALK receptor tyrosine kinase fusion oncoprotein manifested increased expression of PD‐L2 at both the mRNA and protein levels. Furthermore, treatment of NSCLC cell lines that harbor such driver oncogenes with corresponding EGFR or ALK tyrosine kinase inhibitors or depletion of EGFR or ALK by small interfering RNA transfection suppressed expression of PD‐L2, demonstrating that activating EGFR mutations or echinoderm microtubule associated protein like 4 gene (EML4)–ALK receptor tyrosine kinase gene (ALK) fusion intrinsically induce PD‐L2 expression. We also found that interferon gamma (IFN‐&ggr;) extrinsically induced expression of PD‐L2 through signal transducer and activator of transcription 1 signaling in NSCLC cells. Oncogene‐driven expression of PD‐L2 in NSCLC cells was inhibited by knockdown of the transcription factors signal transducer and activator of transcription 3 (STAT3) or c‐FOS. IFN‐&ggr; also activated STAT3 and c‐FOS, suggesting that these proteins may also contribute to the extrinsic induction of PD‐L2 expression. Conclusions: Expression of PD‐L2 is induced intrinsically by activating EGFR mutations or EML4‐ALK fusion and extrinsically by IFN‐&ggr;, with STAT3 and c‐FOS possibly contributing to both intrinsic and extrinsic pathways. Our results thus provide insight into the complexity of tumor immune escape in NSCLC.

中文翻译:

癌基因驱动的非小细胞肺癌中 PD-L2 表达的内在和外在调节

简介:程序性细胞死亡配体 2 (PD-L2) 与程序性细胞死亡 1 的相互作用与肿瘤免疫逃逸有关。然而,肿瘤细胞中 PD-L2 表达的调节仍不清楚。我们在这里检查了 NSCLC 中 PD-L2 表达的内在和外在调节。方法:通过逆转录和实时聚合酶链反应分析以及流式细胞术评估 PD-L2 表达。结果: BEAS-2B 细胞稳定表达 EGFR 的活化突变形式或棘皮动物微管相关蛋白如 4 (EML4)-ALK 受体酪氨酸激酶融合癌蛋白,在 mRNA 和蛋白质水平上均表现出 PD-L2 表达增加。此外,用相应的 EGFR 或 ALK 酪氨酸激酶抑制剂治疗携带此类驱动癌基因的 NSCLC 细胞系或通过小干扰 RNA 转染消除 EGFR 或 ALK 抑制 PD-L2 的表达,表明激活 EGFR 突变或棘皮动物微管相关蛋白如 4 基因( EML4)–ALK 受体酪氨酸激酶基因 (ALK) 融合本质上诱导 PD-L2 表达。我们还发现干扰素 γ (IFN-&ggr;) 通过信号转导和转录 1 信号激活剂在 NSCLC 细胞中外源性诱导 PD-L2 的表达。通过敲低转录因子信号转导和转录激活因子 3 (STAT3) 或 c-FOS,可抑制 NSCLC 细胞中 PD-L2 癌基因驱动的表达。干扰素-> 还激活了 STAT3 和 c-FOS,表明这些蛋白质也可能有助于 PD-L2 表达的外在诱导。结论:PD-L2 的表达是通过激活 EGFR 突变或 EML4-ALK 融合来内在地诱导,而外在地由 IFN-&ggr; 诱导,STAT3 和 c-FOS 可能对内在和外在途径都有贡献。因此,我们的结果提供了对 NSCLC 中肿瘤免疫逃逸复杂性的洞察。
更新日期:2018-07-01
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