PD-L1 is upregulated by EBV-driven LMP1 through NF-κB pathway and correlates with poor prognosis in natural killer/T-cell lymphoma.
PD-L1 is upregulated by EBV-driven LMP1 through NF-κB pathway and correlates with poor prognosis in natural killer/T-cell lymphoma.
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PD-L1 通过 NF-kappa B 途径被 EBV 驱动的 LMP1 上调，并与自然杀伤/T 细胞淋巴瘤的不良预后相关
DOI：
10.1186/s13045-016-0341-7
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发表时间：
2016-10-13
影响因子：
28.5
通讯作者：
Wang L
中科院分区：
文献类型：
--
作者：
Bi XW;Wang H;Zhang WW;Wang JH;Liu WJ;Xia ZJ;Huang HQ;Jiang WQ;Zhang YJ;Wang L
自然杀伤/T细胞淋巴瘤（NKTCL）是一种EB病毒（EBV）相关的高度侵袭性淋巴瘤。治疗结果仍然不理想，特别是对于晚期或复发性疾病。程序性细胞死亡受体1（PD-1）和PD配体1（PD-L1）已成为各种恶性肿瘤的有希望的治疗靶点，但它们在NKTCL发病机制中的作用及其与EBV的相互作用仍有待研究。分别通过蛋白质印迹、定量实时PCR和酶联免疫吸附测定以及流式细胞术测量NK-92（EBV阴性）和SNK-6（EBV阳性）细胞中PD-L1的表达。将携带潜伏膜蛋白1（LMP 1）的慢病毒载体转染到NK-92细胞中以检查LMP 1与PD-L1表达之间的相关性。在用携带LMP 1的载体或阴性对照载体转染的NK-92细胞以及SNK-6细胞中测量LMP 1信号传导下游途径中的蛋白质。回顾性分析安阿伯I~II期NKTCL患者肿瘤标本PD-L1表达及血清可溶性PD-L1浓度，分析其预后意义。PD-L1在SNK-6细胞中的表达在蛋白和mRNA水平上均显著高于NK-92细胞。与转染阴性对照载体的NK-92细胞相比，转染携带LMP 1的慢病毒载体的NK-92细胞中PD-L1的表达显著上调。与阴性对照相比，MAPK/NF-κB通路中的蛋白在表达LMP 1的NK-92细胞中上调。这些蛋白质的选择性抑制剂诱导表达LMP 1的NK-92细胞以及SNK-6细胞中PD-L1表达的显著下调。血清可溶性PD-L1浓度高（≥3.4 ng/ml）或肿瘤标本中PD-L1表达百分比高（≥ 38%）的患者与其对应患者相比，治疗缓解率显著降低，生存期显著降低。血清中高浓度的可溶性PD-L1和肿瘤组织中高比例的PD-L1表达是I~II期NKTCL患者的独立不良预后因素。NKTCL中PD-L1的表达与LMP 1的表达呈正相关，这可能是由MAPK/NF-κB通路介导的。PD-L1在血清和肿瘤组织中的表达对早期NKTCL具有重要的预后价值。本文的在线版本（doi：10.1186/s13045-016-0341-7）包含补充材料，可供授权用户使用。
Natural killer/T-cell lymphoma (NKTCL) is an Epstein–Barr virus (EBV)-associated, highly aggressive lymphoma. Treatment outcome remains sub-optimal, especially for advanced-stage or relapsed diseases. Programmed cell death receptor 1 (PD-1) and PD ligand 1 (PD-L1) have become promising therapeutic targets for various malignancies, but their role in the pathogenesis and their interactions with EBV in NKTCL remains to be investigated. Expression of PD-L1 was measured in NK-92 (EBV-negative) and SNK-6 (EBV-positive) cells by western blot, quantitative real-time PCR and enzyme-linked immunosorbent assay, and flow cytometry, respectively. Latent membrane protein 1 (LMP1)-harboring lentiviral vectors were transfected into NK-92 cells to examine the correlation between LMP1 and PD-L1 expression. Proteins in the downstream pathways of LMP1 signaling were measured in NK-92 cells transfected with LMP1-harboring or negative control vectors as well as in SNK-6 cells. PD-L1 expression on tumor specimens and serum concentration of soluble PD-L1 were collected in a retrospective cohort of patients with Ann Arbor stage I~II NKTCL, and their prognostic significance were analyzed. Expression of PD-L1 was significantly higher in SNK-6 cells than in NK-92 cells, at both protein and mRNA levels. Expression of PD-L1 was remarkably upregulated in NK-92 cells transfected with LMP1-harboring lentiviral vectors compared with those transfected with negative control vectors. Proteins in the MAPK/NF-κB pathway were upregulated in LMP1-expressing NK-92 cells compared with the negative control. Selective inhibitors of those proteins induced significant downregulation of PD-L1 expression in LMP1-expressing NK-92 cells as well as in SNK-6 cells. Patients with a high concentration of serum soluble PD-L1 (≥3.4 ng/ml) or with a high percentage of PD-L1 expression in tumor specimens (≥38 %) exhibited significantly lower response rate to treatment and remarkably worse survival, compared with their counterparts. A high concentration of serum soluble PD-L1 and a high percentage of PD-L1 expression in tumor specimens were independent adverse prognostic factors among patients with stage I~II NKTCL. PD-L1 expression positively correlated LMP1 expression in NKTCL, which was probably mediated by the MAPK/NF-κB pathway. PD-L1 expression in serum and tumor tissues has significant prognostic value for early-stage NKTCL. The online version of this article (doi:10.1186/s13045-016-0341-7) contains supplementary material, which is available to authorized users.
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影响因子：
--
作者：
Fang W;Hong S;Chen N;He X;Zhan J;Qin T;Zhou T;Hu Z;Ma Y;Zhao Y;Tian Y;Yang Y;Xue C;Tang Y;Huang Y;Zhao H;Zhang L
通讯作者：
Zhang L
影响因子：
2.9
作者：
Gru AA;Haverkos BH;Freud AG;Hastings J;Nowacki NB;Barrionuevo C;Vigil CE;Rochford R;Natkunam Y;Baiocchi RA;Porcu P
通讯作者：
Porcu P
影响因子：
--
作者：
Derks S;Liao X;Chiaravalli AM;Xu X;Camargo MC;Solcia E;Sessa F;Fleitas T;Freeman GJ;Rodig SJ;Rabkin CS;Bass AJ
通讯作者：
Bass AJ
DOI：
10.1016/j.ijrobp.2013.08.040
发表时间：
2013-12-01
影响因子：
7
作者：
Bi, Xi-Wen;Li, Ye-Xiong;Dai, Jian-Rong
通讯作者：
Dai, Jian-Rong
DOI：
10.1158/1078-0432.ccr-13-0855
发表时间：
2013-07-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Chen BJ;Chapuy B;Ouyang J;Sun HH;Roemer MG;Xu ML;Yu H;Fletcher CD;Freeman GJ;Shipp MA;Rodig SJ
通讯作者：
Rodig SJ