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中华肝脏外科手术学电子杂志

中华肝脏外科手术学电子杂志 ›› 2020, Vol. 09 ›› Issue (03) : 254 -259. doi: 10.3877/cma.j.issn.2095-3232.2020.03.012

所属专题： 文献；

临床研究

肝癌患者循环肿瘤细胞PD-L1表达及其临床意义
林俊龙1, 黄贻培1, 罗伟鑫1, 许磊波1, 刘超1,†()   
  1. 1. 510120　广州，中山大学孙逸仙纪念医院胆胰外科
  • 收稿日期:2020-02-27 出版日期:2020-06-10
  • 通信作者: 刘超
  • 基金资助:
    广东省自然科学基金(2017A030311002); 广东省科技计划项目(2017A020215196); 中山大学青年教师培育项目(17ykpy44)

Classification of PD-L1 in circulating tumor cells and its clinical significance in patients with primary liver cancer

Junlong Lin1, Yipei Huang1, Weixin Luo1, Leibo Xu1, Chao Liu1,†()   

  1. 1. Department of Hepatoliary and Pancreatic Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
  • Received:2020-02-27 Published:2020-06-10
  • Corresponding author: Chao Liu
  • About author:
    Corresponding author: Liu Chao, Email:
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引用本文：

林俊龙, 黄贻培, 罗伟鑫, 许磊波, 刘超. 肝癌患者循环肿瘤细胞PD-L1表达及其临床意义[J]. 中华肝脏外科手术学电子杂志, 2020, 09(03): 254-259.

Junlong Lin, Yipei Huang, Weixin Luo, Leibo Xu, Chao Liu. Classification of PD-L1 in circulating tumor cells and its clinical significance in patients with primary liver cancer[J]. Chinese Journal of Hepatic Surgery(Electronic Edition), 2020, 09(03): 254-259.

目的

探讨原发性肝癌（肝癌）患者外周血循环肿瘤细胞（CTC）的程序性死亡-配体1（PD-L1）表达及其与肝癌患者临床病理特征的关系。

方法

回顾性分析2017年1月至2019年12月中山大学孙逸仙纪念医院收治的30例肝癌患者临床资料。患者均签署知情同意书，符合医学伦理学规定。其中男27例，女3例；年龄29～77岁，中位年龄51岁。多重RNA原位分析检测患者外周血中CTC分型及其PD-L1表达水平，分析PD-L1表达与临床病理特征之间的相关性。相关性分析采用χ2检验或Fisher确切概率法。

结果

共检出CTC 275个，其中上皮型82个，间质型51个，混合型142个。混合型PD-L1平均表达水平为0.89，明显高于上皮型的0.55及间质型的0.49。混合型CTC为主型肝癌患者数量及PD-L1表达水平亦明显高于其他分型患者。PD-L1阳性的CTC分型与患者肝硬化及肝被膜侵犯相关（χ2=9.707，7.153；P<0.05）。肝癌患者平均PD-L1表达水平仅与患者饮酒史相关（P=0.042）。

结论

肝癌患者CTC以混合型为主，其PD-L1表达水平高于其他分型患者。PD-L1阳性的CTC分型与肝硬化及肝被膜侵犯相关，而PD-L1表达水平仅与患者饮酒史相关。

关键词: 癌，肝细胞, 程序性死亡-配体1, 肿瘤细胞，循环
Objective

To investigate the classification of programmed death-ligand 1 (PD-L1) in the circulating tumor cells (CTCs) of peripheral blood and its relationship with the clinicopathologic feature of patients with primary liver cancer (PLC).

Methods

Clinical data of 30 PLC patients admitted to Sun Yat-sen Memorial Hospital of Sun Yat-sen University from January 2017 to December 2019 were retrospectively analyzed. The informed consents of all patients were obtained and the local ethical committee approval was received. Among them, 27 patients were male and 3 female, aged 29-77 years with a median age of 51 years. The classifications of CTCs in the peripheral blood and the corresponding expression level of PD-L1 were determined by multiple RNA in situ analysis. The correlation between PD-L1 expression and clinicopathologic feature was analyzed by Chi-square test or Fisher's exact probability.

Results

A total of 275 CTCs were detected, including 82 epithelial-type CTCs, 51 interstitial-type CTCs and 142 mixed-type CTCs. The average expression level of PD-L1 in the mixed-type CTCs was 0.89, significantly higher than 0.55 in the epithelial-type and 0.49 in the interstitial-type CTCs. The number of PLC patients with mixed-type CTCs and their expression level of PD-L1 were also significantly higher than those with other phenotypes. The classification of CTCs with positive PD-L1 was significantly associated with liver cirrhosis and liver capsule invasion (χ2=9.707, 7.153; P<0.05). The average expression level of PD-L1 in PLC patients was only correlated with the history of alcohol drinking (P=0.042).

Conclusions

The classification of CTCs in PLC patients is mainly mixed-type. Its expression level PD-L1 is higher than those with other phenotypes. The classification of PD-L1-positive CTCs is associated with liver cirrhosis and liver capsule invasion, whereas PD-L1 expression level is only correlated with the alcohol drinking history of PLC patients.

Key words: Carcinoma, hepatocellular, programmed death-ligand 1 (PD-L1), Neoplastic cells, circulating
图1 CTC不同上皮细胞表型标志物及PD-L1表达
表1 肝癌患者外周血CTC分型及其PD-L1表达水平
分型 数量 百分率（%） PD-L1表达水平
CTC表型 ? ? ?
? 上皮型 82个 30 0.55
? 间质型 51个 18 0.49
? 混合型 142个 52 0.89
CTC阳性患者分型 ? ? ?
? 上皮型为主型 5例 17 0.57
? 间质型为主型 6例 20 0.38
? 混合型为主型 11例 37 0.90
? 均匀分布型 8例 26 0.75
表2 PD-L1阳性CTC不同分子表型与肝癌患者临床病理特征的相关性（个）
参数 例数 PD-L1阳性CTC数 PD-L1阳性CTC分型 χ 2值 P值
上皮型 间质型 混合型
年龄（岁） ? ? ? ? ? 5.897 0.052
? ≤50 14 84 16 9 59 ? ?
? >50 16 65 21 11 33 ? ?
饮酒史 ? ? ? ? ? 2.473 0.290
? 无 25 111 24 16 71 ? ?
? 有 5 38 13 4 21 ? ?
乙肝病史 ? ? ? ? ? 1.331 0.514
? 无 11 62 18 9 35 ? ?
? 有 19 87 19 11 57 ? ?
肝硬化 ? ? ? ? ? 9.707 0.008
? 无 8 22 7 7 8 ? ?
? 有 22 127 30 13 84 ? ?
肿瘤数目 ? ? ? ? ? 0.907 0.635
? 单发 18 87 23 13 51 ? ?
? 多发 12 62 14 7 41 ? ?
肿瘤直径（cm） ? ? ? ? ? 1.942 0.379
? ≤5 17 106 23 15 68 ? ?
? >5 13 43 14 5 24 ? ?
静脉癌栓 ? ? ? ? ? 1.927 0.382
? 无 21 114 30 17 67 ? ?
? 有 9 35 7 3 25 ? ?
微血管癌栓 ? ? ? ? ? 2.358 0.308
? 无 15 83 21 14 48 ? ?
? 有 15 66 14 6 44 ? ?
肝被膜侵犯 ? ? ? ? ? 7.153 0.028
? 无 16 88 25 16 47 ? ?
? 有 14 61 12 4 45 ? ?
远处转移 ? ? ? ? ? 4.214 0.122
? 无 23 121 30 13 78 ? ?
? 有 7 28 7 7 14 ? ?
TNM分期 ? ? ? ? ? 1.719 0.423
? Ⅰ/Ⅱ期 14 92 22 10 60 ? ?
? Ⅲ/Ⅳ期 16 57 15 10 32 ? ?
AFP （μg/L） ? ? ? ? ? 0.383 0.826
? ≤400 24 128 32 18 78 ? ?
? >400 6 21 5 2 14 ? ?
HBsAg ? ? ? ? ? 1.404 0.496
? 阴性 16 101 28 13 60 ? ?
? 阳性 14 48 9 7 32 ? ?
表3 外周血CTC中PD-L1高表达与肝癌患者临床病理特征的相关性（例）
参数 例数 PD-L1表达水平 P值
低表达 高表达
年龄（岁） ? ? ? 0.272
? ≤50 14 5 9 ?
? >50 16 10 6 ?
饮酒史 ? ? ? 0.042
? 无 25 15 10 ?
? 有 5 0 5 ?
乙肝病史 ? ? ? 1.000
? 无 11 6 5 ?
? 有 19 9 10 ?
肝硬化 ? ? ? 0.682
? 无 8 5 3 ?
? 有 22 10 12 ?
肿瘤数目 ? ? ? 0.710
? 单发 18 8 10 ?
? 多发 12 7 5 ?
肿瘤直径（cm） ? ? ? 1.000
? ≤5 17 9 8 ?
? >5 13 6 7 ?
静脉癌栓 ? ? ? 0.427
? 无 21 12 9 ?
? 有 9 3 6 ?
微血管癌栓 ? ? ? 0.143
? 无 15 10 5 ?
? 有 15 5 10 ?
肝被膜侵犯 ? ? ? 0.715
? 无 16 9 7 ?
? 有 14 6 8 ?
远处转移 ? ? ? 1.000
? 无 23 12 11 ?
? 有 7 3 4 ?
TNM分期 ? ? ? 1.000
? Ⅰ/Ⅱ期 14 7 7 ?
? Ⅲ/Ⅳ期 16 8 8 ?
AFP（μg/L） ? ? ? 0.651
? ≤400 24 13 11 ?
? >400 6 2 4 ?
HBsAg ? ? ? 0.715
? 阴性 16 9 7 ?
? 阳性 14 6 8 ?
[1]
Wallace MC, Preen D, Jeffrey GP, et al. The evolving epidemiology of hepatocellular carcinoma: a global perspective[J]. Expert Rev Gastroenterol Hepatol, 2015, 9(6):765-779.
[2]
Hartke J, Johnson M, Ghabril M. The diagnosis and treatment of hepatocellular carcinoma[J]. Semin Diagn Pathol, 2017, 34(2):153-159.
[3]
Kythreotou A, Siddique A, Mauri FA, et al. PD-L1[J]. J Clin Pathol, 2018, 71(3):189-194.
[4]
Okita R, Maeda A, Shimizu K, et al. PD-L1 overexpression is partially regulated by EGFR/HER2 signaling and associated with poor prognosis in patients with non-small-cell lung cancer[J]. Cancer Immunol Immunother, 2017, 66(7):865-876.
[5]
Mittendorf EA, Philips AV, Meric-Bernstam F, et al. PD-L1 expression in triple-negative breast cancer[J]. Cancer Immunol Res, 2014, 2(4):361-370.
[6]
Haber DA, Velculescu VE. Blood-based analyses of cancer: circulating tumor cells and circulating tumor DNA[J]. Cancer Discov, 2014, 4(6):650-661.
[7]
Qi LN, Xiang BD, Wu FX, et al. Circulating tumor cells undergoing EMT provide a metric for diagnosis and prognosis of patients with hepatocellular carcinoma[J]. Cancer Res, 2018, 78(16):4731-4744.
[8]
Micalizzi DS, Maheswaran S, Haber DA. A conduit to metastasis: circulating tumor cell biology[J]. Genes Dev, 2017, 31(18):1827-1840.
[9]
Lianidou ES, Markou A. Circulating tumor cells in breast cancer: detection systems, molecular characterization, and future challenges[J]. Clin Chem, 2011, 57(9):1242-1255.
[10]
Hong B, Zu Y. Detecting circulating tumor cells: current challenges and new trends[J]. Theranostics, 2013, 3(6):377-394.
[11]
Singh M, Yelle N, Venugopal C, et al. EMT: Mechanisms and therapeutic implications[J]. Pharmacol Ther, 2018, 182:80-94.
[12]
Mego M, Mani SA, Lee BN, et al. Expression of epithelial-mesenchymal transition-inducing transcription factors in primary breast cancer: the effect of neoadjuvant therapy[J]. Int J Cancer, 2012, 130(4): 808-816.
[13]
Yokobori T, Iinuma H, Shimamura T, et al. Plastin3 is a novel marker for circulating tumor cells undergoing the epithelial-mesenchymal transition and is associated with colorectal cancer prognosis[J]. Cancer Res, 2013, 73(7):2059-2069.
[14]
Bonnomet A, Syne L, Brysse A, et al. A dynamic in vivo model of epithelial-to-mesenchymal transitions in circulating tumor cells and metastases of breast cancer[J]. Oncogene, 2012, 31(33):3741-3753.
[15]
Yu M, Bardia A, Wittner BS, et al. Circulating breast tumor cells exhibit dynamic changes in epithelial and mesenchymal composition[J]. Science, 2013, 339(6119):580-584.
[16]
Bednarz-Knoll N, Alix-Panabières C, Pantel K. Plasticity of disseminating cancer cells in patients with epithelial malignancies[J]. Cancer Metastasis Rev, 2012, 31(3/4):673-687.
[17]
Balar AV, Weber JS. PD-1 and PD-L1 antibodies in cancer: current status and future directions[J]. Cancer Immunol Immunother, 2017, 66(5):551-564.
[18]
El-Khoueiry AB, Sangro B, Yau T, et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial[J]. Lancet, 2017, 389(10088):2492-2502.
[19]
Nicolazzo C, Raimondi C, Mancini M, et al. Monitoring PD-L1 positive circulating tumor cells in non-small cell lung cancer patients treated with the PD-1 inhibitor Nivolumab[J]. Sci Rep, 2016(6): 31726.
[20]
Cao Y, Zhang L, Kamimura Y, et al. B7-H1 overexpression regulates epithelial-mesenchymal transition and accelerates carcinogenesis in skin[J]. Cancer Res, 2011, 71(4):1235-1243.
[21]
Lou Y, Diao L, Cuentas ER, et al. Epithelial-mesenchymal transition is associated with a distinct tumor microenvironment including elevation of inflammatory signals and multiple immune checkpoints in lung adenocarcinoma[J]. Clin Cancer Res, 2016, 22(14):3630-3642.
[22]
Datar I, Schalper KA. Epithelial-mesenchymal transition and immune evasion during lung cancer progression: the chicken or the egg?[J]. Clin Cancer Res, 2016, 22(14):3422-3424.
[23]
Kim S, Koh J, Kim MY, et al. PD-L1 expression is associated with epithelial-to-mesenchymal transition in adenocarcinoma of the lung[J]. Hum Pathol, 2016(58):7-14.
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