程序性细胞死亡受体-1及其配体与肝细胞癌患者预后和临床特征相关性的Meta分析

代鑫; 刘汉林; 程龙; 骆助林; 汪涛

doi:10.3969/j.issn.1001-5256.2022.07.022

程序性细胞死亡受体-1及其配体与肝细胞癌患者预后和临床特征相关性的Meta分析

DOI: 10.3969/j.issn.1001-5256.2022.07.022

代鑫¹,
刘汉林²,
程龙¹,
骆助林¹,
汪涛^1, , ,

1.
中国人民解放军西部战区总医院普通外科，成都 610083
2.
西南医科大学临床医学院，四川泸州 646000

基金项目:

四川省青年科技基金项目 (2016JQ0023);

四川省科学技术厅科研基金 (2020YFSY0022)

利益冲突声明：本研究不存在研究者、伦理委员会成员、受试者监护人以及与公开研究成果有关的利益冲突。

作者贡献声明：代鑫负责资料分析，撰写论文；刘汉林负责数据整理及分析；程龙、骆助林参与论文审校；汪涛负责课题设计、拟定写作思路，指导撰写文章并最后定稿。

详细信息

通信作者:
汪涛，watopo@163.com

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出版历程
- 收稿日期: 2021-11-15
- 录用日期: 2022-01-10
- 出版日期: 2022-07-20

Association of programmed death-1 and programmed death-ligand 1 with the prognosis and clinical features of patients with hepatocellular carcinoma: A meta-analysis

Xin DAI¹,
Hanlin LIU²,
Long CHENG¹,
Zhulin LUO¹,
Tao WANG^{1
, ,
,}

1.
Department of General Surgery, The General Hospital of Western Theater Command, Chengdu 610083, China
2.
School of Clinical Medicine, Southwest Medical University, Luzhou, Sichuan 646000, China

Research funding:

Project of Sichuan Youth Science and Technology Fund (2016JQ0023);

Sichuan Science and Technology Plan Project (2020YFSY0022)

More Information

Corresponding author: WANG Tao, watopo@163.com(ORICD: 0000-0003-4064-8867)

摘要

摘要: 目的系统评价程序性细胞死亡-1(PD-1)和程序性细胞死亡配体-1(PD-L1)的表达对肝细胞癌患者预后的影响。方法检索PubMed、Cochrane Library、Embase、中国生物医学数据库、中国知网、万方等数据库收集相关文献。纳入调查PD-1/PD-L1表达与肝细胞癌患者预后关系的队列研究或病例对照研究。采用RevMan 5.3软件对总生存期(OS)、无瘤生存期(DFS)进行Meta分析。结果共纳入20项符合条件的队列研究或病例对照研究。PD-1的表达与HCC患者的OS无关(HR=0.78, 95%CI: 0.31~1.97, P＜0.05)，但与DFS显著相关(HR=0.38, 95%CI: 0.24~0.58, P＜0.01)；PD-L1的表达与HCC患者的OS显著相关(HR=1.64, 95%CI: 1.26~2.15, P＜0.05)，但与DFS无关(HR=1.48, 95%CI: 0.88~2.49, P＞0.05)。PD-1/PD-L1的表达与肝细胞癌患者临床特征无明显相关性(P＞0.05)。结论 PD-1/PD-L1表达与肝细胞癌患者预后具有相关性，但与临床特征无明显相关性。
- 癌, 肝细胞 /
- 程序性细胞死亡受体-1 /
- 程序性细胞死亡配体-1 /
- Meta分析(主题)
Abstract: Objective To systematically evaluate the influence of the expression of programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) on the prognosis of patients with hepatocellular carcinoma (HCC). Methods Related databases, such as PubMed, The Cochrane Library, Embase, CBM, CNKI, and Wanfang Data, were searched to collect related articles, and the cohort studies or case-control studies on the association of the expression of PD-1 and PD-L1 with the prognosis of HCC patients were included. RevMan 5.3 software was used to perform a meta-analysis of overall survival (OS) and disease-free survival (DFS). Results A total of 20 eligible cohort studies or case-control studies were included. The expression of PD-1 was not associated with the OS of HCC patients (hazard ratio [HR]=0.78, 95% confidence interval [CI]: 0.31-1.97, P < 0.05), while it was significantly associated with DFS (HR=0.38, 95%CI: 0.24-0.58, P < 0.01). The expression of PD-L1 was significantly associated with the OS of HCC patients (HR=1.64, 95%CI: 1.26-2.15, P < 0.05), but it was not associated with DFS (HR=1.48, 95%CI: 0.88-2.49, P > 0.05). In addition, the expression of PD-1 and PD-L1 was not significantly associated with the clinical features of HCC patients (P > 0.05). Conclusion The expression of PD-1 and PD-L1 is associated with the prognosis of HCC patients, with no significant association with clinical features.
- Carcinoma, Hepatocellular /
- Programmed Cell Death Receptor /
- Programmed Cell Death 1 Ligand /
- Meta-Analysis as Topic

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图 1 纳入文献的筛选流程图

Figure 1. Screening flow chart of included literature

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图 2 PD-1表达与OS关系的森林图

Figure 2. Forest map of the relationship between PD-1 expression and OS

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图 3 PD-L1表达与OS关系的森林图

Figure 3. Forest map of the relationship between PD-L1 expression and OS

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图 4 PD-1表达与DFS关系的森林图

Figure 4. Forest map of the relationship between PD-1 expression and DFS

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图 5 PD-L1表达与DFS关系的森林图

Figure 5. Forest map of the relationship between PD-L1 expression and DFS

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图 6 PD-L1表达与OS和DFS关系的漏斗图

注：a，OS；b，DFS。

Figure 6. Funnel plot of PD-L1 expression in relation to OS and DFS

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图 7 PD-1/PD-L1表达与OS和DFS关系的敏感性分析

注：a，PD-L1(OS)；b，PD-L1(DFS)；c，PD-1(OS)；d，PD-1(DFS)。

Figure 7. Sensitivity analysis of the relationship between PD-1/PD-L1 expression and OS and DFS

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表 1 纳入文献基本特征

Table 1. Basic characteristics of included literature

作者	时间	国家	样本量	方法	表达位置	结局	治疗	研究类型
Chang^[9]	2019	中国	120	抗体阵列分析	血清	OS、DFS	手术	回顾性病例对照研究
Chang^[10]	2018	中国	145	免疫组化	肿瘤浸润性淋巴细胞	OS、DFS	综合	回顾性病例对照研究
Chang^[11]	2017	韩国	146	免疫组化	肿瘤组织	DFS	手术	回顾性病例对照研究
Dai^[12]	2018	中国	90	免疫组化	肿瘤组织	OS	手术	回顾性病例对照研究
Finkelmeier^[13]	2016	德国	215	酶联免疫吸附试验	血清	OS	-	回顾性病例对照研究
Gao^[14]	2009	中国	240	免疫组化	肿瘤组织	OS、DFS	手术	队列研究
Han^[15]	2019	中国	81	酶联免疫吸附试验	血清	OS、DFS	-	回顾性病例对照研究
Hu^[16]	2018	中国	136	免疫组化	肿瘤组织	OS	手术	回顾性病例对照研究
Huang^[17]	2017	中国	411	免疫组化	肿瘤组织	OS	手术	回顾性病例对照研究
Jung^[18]	2017	韩国	85	免疫组化	肿瘤组织	OS、DFS	手术	回顾性病例对照研究
Kan^[19]	2015	中国	128	免疫组化	肿瘤组织	OS	手术	回顾性病例对照研究
Li^[20]	2017	中国	83	酶联免疫吸附试验	血清	OS	-	队列研究
Liu^[21]	2018	中国	453	免疫组化	肿瘤组织	OS	手术	回顾性病例对照研究
Pei^[22]	2019	中国	143	免疫组化	肿瘤组织	OS	手术	回顾性病例对照研究
Semaan^[23]	2017	德国	176	免疫组化	肿瘤组织	OS	手术	回顾性病例对照研究
Sideras^[24]	2017	荷兰	146	免疫组化	肿瘤组织	DFS	手术	回顾性病例对照研究
Umemoto^[25]	2015	日本	80	免疫组化	肿瘤组织	OS	手术	回顾性病例对照研究
Xie^[26]	2016	中国	90	免疫组化	肿瘤组织	OS、DFS	手术	队列研究
Zeng^[27]	2011	中国	109	流式细胞检测分析	血清	OS	-	回顾性病例对照研究
Zhang^[28]	2018	中国	46	免疫组化	肿瘤组织	OS	手术	回顾性病例对照研究

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表 2 纳入文献质量评价

Table 2. Including literature quality evaluation

作者	时间	国家	对象的选择(分)				可比性(分)	结局评估(分)			得分(分)
作者	时间	国家	a	b	c	d	e	f	g	h	得分(分)
Chang^[9]	2019	中国	1	1	1	1	1	1	1	-	7
Chang^[10]	2018	中国	1	1	1	1	1	1	1	1	8
Chang^[11]	2017	韩国	1	1	1	1	1	1	1	1	8
Dai^[12]	2018	中国	1	1	1	1	1	1	1	1	8
Finkelmeier^[13]	2016	德国	1	1	1	1	1	1	1	1	8
Gao^[14]	2009	中国	1	1	1	1	1	1	-	-	6
Han^[15]	2019	中国	1	1	1	1	1	1	1	-	7
Hu^[16]	2018	中国	1	1	1	1	1	1	1	-	6
Huang^[17]	2017	中国	1	1	1	1	1	1	1	1	8
Jung^[18]	2017	韩国	1	1	1	1	1	1	1	-	7
Kan^[19]	2015	中国	1	1	1	1	1	1	1	-	7
Li^[20]	2017	中国	1	1	1	1	1	1	1	1	8
Liu^[21]	2018	中国	1	1	1	1	1	1	1	1	8
Pei^[22]	2019	中国	1	1	1	1	1	1	-	-	6
Semaan^[23]	2017	德国	1	1	1	1	1	1	1	1	8
Sideras^[24]	2017	荷兰	1	1	1	1	1	1	1	1	8
Umemoto^[25]	2015	日本	1	1	1	1	1	1	-	-	6
Xie^[26]	2016	中国	1	1	1	1	1	1	-	-	6
Zeng^[27]	2011	中国	1	1	1	1	1	1	1	-	7
Zhang^[28]	2018	中国	1	1	1	1	1	1	1	1	8
注：a为暴露队列的代表性；b为非暴露队列的选择；c为暴露因素确定；d为研究起始前尚无要观察的结局事件；e为基于设计或分析所得的队列的可比性；f为结局事件的评价；g为随访时间足够长；h为随访的完整性。

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表 3 PD-1表达与HCC临床特征的Meta分析

Table 3. Meta-analysis of PD-1 expression and clinical characteristics of HCC

临床特征	研究数量	例数	OR(95%CI)	P值	异质性检验
临床特征	研究数量	例数	OR(95%CI)	P值	I²值	P值	模型
年龄(＞50岁/＜50岁)	3	406	1.39(0.92~2.12)	0.12	0%	0.46	混合
性别(男/女)	3	406	1.32(0.76~2.28)	0.33	0%	0.41	混合
AFP(高/低)	3	406	1.01(0.30~3.36)	0.99	87%	0.000 4	随机
肿瘤大小(＜5 cm/＞5 cm)	3	406	0.52(0.10~2.83)	0.45	92%	＜0.000 01	随机
肝炎(是/否)	2	265	0.63(0.29~1.37)	0.24	0%	0.70	混合
肿瘤数量(单发/多发)	3	410	0.78(0.46~1.31)	0.34	46%	0.16	混合
BCLC分期(A/B)	3	265	1.03(0.47~2.24)	0.94	50%	0.16	混合

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表 4 PD-L1表达与HCC临床特征的Meta分析

Table 4. Meta-analysis of PD-1 expression and clinical characteristics of HCC

临床特征	研究数量	例数	OR(95%CI)	P值	异质性检验
临床特征	研究数量	例数	OR(95%CI)	P值	I²值	P值	模型
年龄(＞50岁/＜50岁)	11	1541	0.96(0.76~1.21)	0.74	0	0.53	混合
性别(男/女)	14	2208	1.25(0.95~1.65)	0.11	0	0.82	混合
AFP (高/低)	10	1354	1.30(0.88~1.94)	0.19	56%	0.01	随机
肿瘤大小(＜5 cm/＞5 cm)	11	1774	1.13(0.69~1.84)	0.62	76%	＜0.000 1	随机
肝炎(是/否)	12	1972	1.18(0.88~1.58)	0.28	26%	0.19	混合
肿瘤数量(单发/多发)	9	1595	1.07(0.81~1.41)	0.26	20%	0.64	混合
TNM分期(晚期/早期)	6	1115	1.10(0.78~1.53)	0.59	27%	0.23	混合
分化程度(高/低)	7	1224	0.82(0.61~1.12)	0.21	47%	0.08	混合
肝炎(是/否)	6	926	1.24(0.69~2.22)	0.48	59%	0.03	随机
血管侵犯(是/否)	10	1665	1.17(0.67~2.06)	0.58	77%	＜0.000 1	随机

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