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系统性免疫炎症指数与非小细胞肺癌患者预后关系的研究进展

陈晓博, 王倩, 李庆霞

陈晓博, 王倩, 李庆霞. 系统性免疫炎症指数与非小细胞肺癌患者预后关系的研究进展[J]. 肿瘤防治研究, 2021, 48(6): 652-656. DOI: 10.3971/j.issn.1000-8578.2021.20.1381
引用本文: 陈晓博, 王倩, 李庆霞. 系统性免疫炎症指数与非小细胞肺癌患者预后关系的研究进展[J]. 肿瘤防治研究, 2021, 48(6): 652-656. DOI: 10.3971/j.issn.1000-8578.2021.20.1381
CHEN Xiaobo, WANG Qian, LI Qingxia. Research Progress on Relation Between SII and Prognosis of Non-small Cell Lung Cancer Patients[J]. Cancer Research on Prevention and Treatment, 2021, 48(6): 652-656. DOI: 10.3971/j.issn.1000-8578.2021.20.1381
Citation: CHEN Xiaobo, WANG Qian, LI Qingxia. Research Progress on Relation Between SII and Prognosis of Non-small Cell Lung Cancer Patients[J]. Cancer Research on Prevention and Treatment, 2021, 48(6): 652-656. DOI: 10.3971/j.issn.1000-8578.2021.20.1381

系统性免疫炎症指数与非小细胞肺癌患者预后关系的研究进展

详细信息
    作者简介:

    陈晓博(1994-),女,硕士在读,主要从事肺癌的基础和临床研究

    通讯作者:

    李庆霞(1973-),女,博士,主任医师,主要从事肺癌的基础和临床研究,E-mail: lqx73@163.com

  • 中图分类号: R374.2

Research Progress on Relation Between SII and Prognosis of Non-small Cell Lung Cancer Patients

More Information
  • 摘要:

    肺癌是世界上常见的恶性肿瘤,其中非小细胞肺癌(NSCLC)占肺癌的大多数。虽然在手术、化学药物治疗、放射治疗、靶向治疗、免疫治疗中NSCLC患者的总体生存率在不断改善,但部分患者预后仍较差。炎性反应在肿瘤的发生、进展和转移中均起着重要作用。因此,与炎性反应相关的全血细胞计数将会是预测NSCLC预后的有效指标。由中性粒细胞、淋巴细胞、血小板系统组成的系统免疫炎症指数(SII)能全面反映宿主全身炎症及免疫状态,与其他炎症指标如C反应蛋白/白蛋白值(CAR)、晚期肺癌炎症指数(ALI)、预后营养指数(PNI)等的联合检测,可以增加对NSCLC患者预后的预测效能。此外,SII检测成本低廉、操作简单、获取方便,易于在临床中运用。本文就SII与NSCLC预后关系的研究进展综述如下。

     

    Abstract:

    Lung cancer is a common malignant tumor in the world and NSCLC accounts for the majority. Although the overall survival rate of patients with NSCLC is improving through surgery, chemotherapy, radiotherapy, targeted therapy and immunotherapy, the prognosis of some patients is still poor. Inflammatory response plays an important role in the occurrence, progress and metastasis of tumors. Therefore, the whole blood cell count associated with inflammatory response will be an effective index to predict the prognosis of NSCLC. The systemic immune-inflammatory index (SII), composed of neutrophils, lymphocytes and platelet systems, can fully reflect the systemic inflammation and immune status of the host, and can be combined with other inflammatory indexes such as C-reactive protein/albumin value (CAR), advanced lung cancer inflammatory index (ALI) and prognostic nutritional index (PNI). It can increase the predictive efficacy of NSCLC patieats' prognosis. In addition, SII has the advantages of low cost, simple operation and convenient acquisition, and is easy to be used in clinic. This paper reviews the research progress of the relation between SII and the prognosis of NSCLC.

     

  • 鼻咽癌(nasopharyngeal carcinoma, NPC)是我国以及东南亚地区常见的头颈部恶性肿瘤之一,死亡率约为1.74/100 000[1]。鼻咽癌治疗后复发病例占治疗失败病例的30%,复发的鼻咽癌往往具有肿瘤乏氧[2]、肿瘤侵袭能力增强、治疗前贫血[3]等更加恶劣的病理学表现,从而加大复发后的治疗难度。研究表明,鼻咽癌复发患者5年内生存率仅为30%[4]。乏氧诱导因子-1α(hypoxia induce factor-1α, HIF-1α)是机体应对乏氧的主要效应因子,已经被证实与肿瘤缺氧、侵袭能力增强等细胞生物学行为密切相关[5]。程序死亡受体-配体1(programmed death ligand 1, PD-L1)是程序性死亡受体1(programmed death 1, PD-1)的配体之一,可以抑制T细胞的活化,诱导肿瘤患者体内T细胞凋亡从而导致肿瘤细胞免疫逃逸[6]。临床研究表明在口腔癌和肺癌中PD-L1的表达与HIF-1α有关[7-8]。因此,乏氧诱导的鼻咽癌恶化很可能与HIF-1α调节PD-L1的表达相关,但具体调控机制尚未明确。本实验以鼻咽癌细胞为研究对象,通过在乏氧条件下沉默HIF-1α基因,检测细胞增殖和细胞凋亡率,研究了乏氧条件下鼻咽癌中HIF-1α对于鼻咽癌细胞生物学行为的影响,并且初步探讨鼻咽癌细胞中HIF-1α通过上调PD-L1促进鼻咽癌恶性发展的相关分子机制。

    人类鼻咽癌细胞系CNE2(低分化癌),由中山肿瘤防治中心赠予。

    RPMI 1640培养基购自美国Hyclone公司,胎牛血清(Fetal bovine serum, FBS)、青霉素-链霉素双抗浓缩液(×100)、无血清培养基Opti-MEM、胰酶(Trypsin-EDTA)购自美国Gibco公司;核糖核酸酶抑制剂、MTT细胞增殖检测剂购自美国Sigma公司;Triton-X 100购自北京中杉金桥生物技术有限公司;HIF-1α小鼠单克隆抗体(93kD)、STAT3兔单克隆抗体(88kD)、PSTAT3兔单克隆抗体(88kD)、PD-L1兔单克隆抗体(40~45kD)、兔多抗GAPDH(37kD)均购自英国Abcam公司;RNA提取试剂TRIzol reagent、LipofectamineTM 2000购自美国Invitrogen公司;反转录试剂盒、PCR Master Mix试剂盒购自加拿大Fermentas公司;siRNA及PCR目标基因引物的合成由北京擎科新业生物技术有限公司提供。

    采用10%FBS、1%青霉素和链霉素的RPMI 1640培养基培养细胞。取对数生长期、生长状态良好的CNE2细胞,进行细胞计数,并以每孔2×105个细胞接种于6孔板,37℃、5%CO2培养箱中培养。设常氧组、乏氧组、HIF-1α-siRNA+乏氧组、NC-siRNA+乏氧组四组进行实验。常氧组的细胞在20%O2中培养,乏氧组在1%O2中培养,HIF-1α-siRNA+乏氧组的细胞在1%O2中培养并转染HIF-1α-siRNA,NC-siRNA+乏氧组在1%O2中培养并转染NC-siRNA。按照脂质体LipofectamineTM2000转染试剂说明书进行细胞转染,将根据HIF-1α序列设计筛选的HIF-1α-siRNA转染至CNE2细胞,同时另设一组CNE2细胞转染无意义的干扰序列NC-siRNA作为对照。培养48 h后进行后续实验,转染序列见表 1

    表  1  转染序列
    Table  1  Transfection sequence
    下载: 导出CSV 
    | 显示表格

    按照不同的条件处理细胞以后,弃去培养基停止培养,加入TRIzol提取总RNA,按照反转录试剂盒说明书将RNA反转录成cDNA,PCR产物通过1.2%琼脂糖凝胶电泳分离,于凝胶成像仪中成像。同时按照荧光定量PCR试剂盒说明书检测mRNA水平。反应条件为:50℃ 2 min,95℃ 10 min;95℃ 30 s,60℃ 30 s,40个循环。引物序列见表 2。最终数据采用2-ΔΔCt方法进行分析(检测siRNA敲低效率)。通过RT-PCR检测HIF-1α、PD-L1及STAT3分子的mRNA表达水平。

    表  2  引物序列及扩增片段长度
    Table  2  Primer sequence and amplified fragment length
    下载: 导出CSV 
    | 显示表格

    将各组细胞按照不同条件处理后,弃去培养基终止培养后,用0.25%的胰酶消化,按照每孔5×104个/毫升接种至96孔板,按照不同条件培养过夜后,每孔加入10 μl MTT,37℃孵育4 h后,加入150 μl DMSO,最后用酶标仪测量568 nm波长处的OD值,细胞存活率(%)=(实验组OD均值/对照组OD均值)×100%。

    将各组不同细胞按不同条件处理后,48 h收集各组细胞,按AnnexinV-APC/7-AAD细胞凋亡检测试剂盒说明书进行检测,加入Bind Buffer混匀,反应15 min后加入Annexin-APC检测试剂混匀,最后上流式细胞仪检测。

    按照不同条件处理细胞各组细胞后,弃去培养基终止培养,每皿加入100 μl细胞裂解液(PMSF: 裂解液=1:100)裂解细胞,冰上裂解30 min后收集裂解的细胞,按照BSA试剂盒测量提取的蛋白浓度。将提取的蛋白用5×蛋白上样缓冲液混合后,在沸水中煮沸变性。样品用10%分离胶或者8%分离胶以及5%浓缩胶进行电泳分离,电转、封闭之后,4℃孵育一抗过夜(GADPH: 1:1 000,STAT3: 1:1 500, PSTAT3: 1:200 000, HIF-1α: 1:1 000, PD-L1: 1:1 000),第二日用HRP标记羊抗兔二抗室温孵育2 h,最后用凝胶成像仪成像,BandScan5.0分析胶片灰度值。

    数据应用均数±标准差(x±s)表示,组间比较采用单因素方差分析。实验数据采用SPSS17.0软件进行分析;双侧检验P < 0.05为差异有统计学意义。

    我们针对HIF-1α设计合成了三条不同的siRNA序列,筛选出其中敲低效率最高的一条,即HIF-1α-siRNA-2进行后续实验,见图 1A。MTT实验结果显示乏氧条件下细胞增殖率显著大于常氧组(均P=0.000),见图 1B。与常氧组相比,HIF-1α-siRNA+乏氧显著降低了细胞增殖率(P=0.000);与NC-siRNA+乏氧组相比,HIF-1α-siRNA+乏氧也显著降低了细胞增殖(P=0.000)。由此可得,乏氧条件下HIF-1α在CNE2的细胞增殖中发挥了重要作用。

    图  1  转染HIF-1α-siRNA后CNE2细胞对HIF-1α基因的沉默效率(A)和MTT检测不同处理条件下CNE2细胞的增殖水平(B)
    Figure  1  Silencing efficiency of HIF-1α in CNE2 cells(A) and proliferation of CNE2 cells under different treatment conditions detected by MTT(B)
    ***: P < 0.001.

    流式细胞术显示,乏氧条件下细胞凋亡率与常氧培养条件下细胞凋亡率无明显差异。相比于乏氧组的细胞,乏氧条件下转染HIF-1α-siRNA后显著增加了细胞凋亡率(P=0.000)。此外,HIF-1α-siRNA+乏氧组的细胞凋亡率也明显大于NC-siRNA+乏氧组(P=0.001),见图 2。实验结果提示靶向沉默HIF-1α基因能够促进人鼻咽癌细胞CNE2的凋亡。

    图  2  流式细胞术检测不同处理条件下CNE2细胞的凋亡水平
    Figure  2  Apoptosis of CNE2 cells under different treatment conditions detected by flow cytometry

    RT-PCR检测显示,乏氧组的HIF-1α mRNA水平显著高于常氧组(P=0.004),HIF-1α-siRNA转染后CNE2细胞HIF-1α mRNA水平显著下降,显著低于乏氧组(P=0.000)和NC-siRNA+乏氧组(P=0.000),显示转染成功,见图 3。HIF-1α-siRNA+乏氧组的PD-L1 mRNA水平显著低于乏氧组(P=0.000)和NC-siRNA+乏氧组(P=0.000),显示HIF-1α mRNA水平与PD-L1 mRNA水平呈正比。此外,乏氧组的STAT3 mRNA表达水平相比常氧组显著上升(P=0.009),HIF-1α-siRNA+乏氧组的STAT3 mRNA水平显著低于乏氧组(P=0.001)和NC-siRNA+乏氧组(P=0.001),见图 4。结果表明HIF-1α mRNA水平与PD-L1 mRNA水平成正相关,且STAT3可能是HIF-1α正性调控PD-L1的关键信号因子。

    图  3  RT-PCR检测CNE2细胞中HIF-1α、PD-L1及STAT3的表达
    Figure  3  HIF-1α, PD-L1 and STAT3 expression in CNE2 cells detected by RT-PCR
    1: Normoxia; 2: Hypoxia; 3: HIF-1α-siRNA+Hypoxia; 4: NC-siRNA+Hypoxia.
    图  4  不同条件下CNE2细胞中HIF-1α(A)、PD-L1(B)及STAT3(C)mRNA表达水平的变化
    Figure  4  HIF-1α(A), PD-L1(B) and STAT3(C) mRNA expression in CNE2 cells under different conditions
    **: P < 0.01; ***: P < 0.001; 1: Normoxia; 2: Hypoxia; 3: HIF-1α-siRNA+Hypoxia; 4: NC-siRNA+Hypoxia.

    Western blot检测结果显示,乏氧组的HIF-1α蛋白水平显著高于常氧组(P=0.004),HIF-1α-siRNA转染后的CNE2细胞HIF-1α分子蛋白水平显著下降,显著低于乏氧组(P=0.001)和NC-siRNA+乏氧组(P=0.001)。同时,HIF-1α-siRNA+乏氧组的PD-L1蛋白水平显著低于乏氧组(P=0.017)和NC-siRNA+乏氧组(P=0.0017),显示HIF-1α分子蛋白水平与PD-L1蛋白水平成正比。此外,相比常氧组,乏氧组的STAT3和pSTAT3蛋白表达水平均显著上升(P=0.011),HIF-1α-siRNA+乏氧组的STAT3蛋白水平显著低于乏氧组(P=0.009)和NC-siRNA+乏氧组(P=0.001),HIF-1α-siRNA+乏氧组的pSTAT3蛋白水平显著低于乏氧组和NC-siRNA+乏氧组(均P < 0.001),见图 5~6。实验结果表明,乏氧条件下,随着HIF-1α诱导PD-L1的高表达,STAT3磷酸化水平也增加。反之,HIF-1α的靶向沉默抑制了PD-L1的表达和STAT3磷酸化水平。我们认为HIF-1α诱导PD-L1表达上调可能通过活化STAT3实现。

    图  5  Western blot检测CNE2细胞中HIF-1α, PD-L1, STAT3及pSTAT3蛋白的表达
    Figure  5  HIF-1α, PD-L1, STAT3 and pSTAT3 protein expression in CNE2 cells detected by Western blot
    1: Normoxia; 2: Hypoxia; 3: HIF-1α-siRNA+Hypoxia; 4: NC-siRNA+Hypoxia.
    图  6  不同条件下CNE2细胞中HIF-1α(A)、PD-L1(B)、STAT3(C)及pSTAT3(D)蛋白表达水平的变化
    Figure  6  HIF-1α(A), PD-L1(B), STAT3(C) and pSTAT3(D) proteins expression in CNE2 cells under different conditions
    *: P < 0.05; **: P < 0.01; ***: P < 0.001; 1: Normoxia; 2: Hypoxia; 3: HIF-1α-siRNA+Hypoxia; 4: NC-siRNA+Hypoxia.

    鼻咽癌是我国最常见的头颈部恶性肿瘤之一,传统的治疗方法难以根治。乏氧在肿瘤微环境中非常常见,且能影响恶性肿瘤的生理状况。HIF-1α是乏氧环境下调控基因的重要转录因子[8]。研究表明,HIF-1α在包括乳腺癌[9]、鼻咽癌及结肠癌等多种人类肿瘤中过度表达,且HIF-1α高表达往往与恶性肿瘤患者的不良预后有关。有研究证明原花青素可以通过降低HIF-1α从而抑制鼻咽癌细胞生长[10]。然而,HIF-1α在鼻咽癌中的具体机制尚不明确。本研究发现,乏氧组HIF-1α高表达下的高增殖率和低凋亡率可被siRNA-HIF-1α转染有效逆转。这些结果证明HIF-1α表达可以促使乏氧条件下鼻咽癌的恶性进展。

    随着免疫治疗的发展,PD-L1的表达水平与鼻咽癌发展开始得到密切关注。PD-L1往往在肿瘤细胞表面高表达,通过与PD-1的结合抑制T细胞活化,促进肿瘤细胞免疫逃逸。研究表明乏氧条件下HIF-1α可能通过调节PD-L1,造成肿瘤细胞免疫耐受,促进癌症恶性发展[11-14]。最新研究发现鼻咽癌白人患者中肿瘤细胞上PD-L1表达与不良结果相关[15]。本研究发现,鼻咽癌细胞中HIF-1α的表达与PD-L1的表达呈显著正相关。除此之外,乏氧条件下,鼻咽癌细胞中STAT3 mRNA和蛋白水平显著高于常氧组,而转染siRNA-HIF-1α逆转了这一现象,同时降低了STAT3的磷酸化水平。已有研究报道STAT3是介导PD-L1表达的调控因子[16],而伊卡利汀可以通过抑制STAT3磷酸化抑制鼻咽癌细胞CNE2的增殖、迁移和侵袭[17]。因此,PD-L1可能是乏氧诱导鼻咽癌恶性进展的重要原因,并且涉及STAT3的活化,这与Xing等[18]研究结论一致。

    PD-L1免疫治疗可能给鼻咽癌治疗带来新的治疗策略。PD-L1抗体阿特珠单抗,Durvalumab已可以用来治疗非小细胞肺癌和膀胱癌[19]。PD1免疫抑制剂联合化学疗法作为转移性鼻咽癌的一线治疗可以缓解91%患者的病情,34%复发鼻咽癌患者的病情[20],IFNβ和抗PD-1的组合可以增强NK细胞对鼻咽癌细胞的细胞毒性[21],但是尚未有临床报导PD-L1抑制剂对鼻咽癌的治疗作用。

    PD-L1是鼻咽癌患者预后的独立影响因素[22],结合本研究发现,PD-L1在免疫耐受中的调控作用将会给鼻咽癌治疗带来新的方向,PD-L1有望为鼻咽癌免疫疗法提供新的分子靶标。另外,本研究在评估PD-L1的表达与临床鼻咽癌患者的相关性,验证PD-L1抑制剂对鼻咽癌的治疗作用等实验方面还待展开,如何使鼻咽癌免疫治疗更优化,需要我们结合更多的实验和大数据分析,进一步探索PD-L1影响鼻咽癌的相关机制,考察以PD-L1为靶点的治疗方案。

    Competing interests: The authors declare that they have no competing interests.
    作者贡献:
    陈晓博:论文构思、撰写及修改
    王倩:参与文献收集及整理
    李庆霞:论文构思、写作指导及审阅
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出版历程
  • 收稿日期:  2020-11-26
  • 修回日期:  2021-02-08
  • 网络出版日期:  2024-01-12
  • 刊出日期:  2021-06-24

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