免疫抑制性因子程序性细胞死亡配体1和T细胞免疫球蛋白黏蛋白3对肝细胞癌患者预后的影响

doi:10.12114/j.issn.1007-9572.2023.0543

中国全科医学 ›› 2026, Vol. 29 ›› Issue (24): 3461-3465.DOI: 10.12114/j.issn.1007-9572.2023.0543

免疫抑制性因子程序性细胞死亡配体1和T细胞免疫球蛋白黏蛋白3对肝细胞癌患者预后的影响

赵思楠¹, 林杉², 康希², 王春燕³, 王顺祥²^,^*()

1．050011　河北省石家庄市，河北医科大学第二医院内分泌科
2．050011　河北省石家庄市，河北医科大学第四医院肝胆外科
3．050011　河北省石家庄市，河北医科大学第四医院消化内科

收稿日期:2023-07-12 修回日期:2025-08-20 出版日期:2026-08-20 发布日期:2026-07-03
通讯作者: 王顺祥
作者贡献：
赵思楠提出研究思路，负责数据收集和论文撰写；林杉负责数据收集、数据整理和统计学分析；康希负责数据收集、数据整理和论文编辑与修改；王春燕负责数据收集、数据整理；王顺祥负责项目管理、思路指导、文章监督管理和审查，并对文章整体负责。
基金资助:
河北省医学科学研究课题计划(20200092)

Impact of Immune Inhibitory Factors Programmed Cell Death Ligand 1 and T Cell Immunoglobulin Mucin-3 on the Prognosis of Hepatocellular Carcinoma Patients

ZHAO Sinan¹, LIN Shan², KANG Xi², WANG Chunyan³, WANG Shunxiang²^,^*()

1. Department of Endocrinology, Second Hospital of Hebei Medical University, Shijiazhuang 050011, China
2. Department of Hepatobiliary Surgery, Fourth Hospital of Hebei Medical University, Shijiazhuang 050011, China
3. Department of Gastroenterology, Fourth Hospital of Hebei Medical University, Shijiazhuang 050011, China

Received:2023-07-12 Revised:2025-08-20 Published:2026-08-20 Online:2026-07-03
Contact: WANG Shunxiang

摘要/Abstract

摘要： 背景肝细胞癌是全球第六大常见癌症，我国每年新增肝细胞癌病例数约为415 000例，约占全球肝癌新发病例总数的一半。肝细胞癌可以通过多种免疫抑制性因子触发免疫逃逸，最终导致肿瘤的进展和转移。程序性细胞死亡配体1（PD-L1）和T细胞免疫球蛋白黏蛋白3（TIM3）作为近年来被发现的两种表达于肝细胞癌的免疫抑制性因子，其与肝癌患者预后的关系目前尚不明确。目的研究分析肝细胞癌PD-L1和TIM3表达水平对患者预后的影响。方法本研究采用回顾性队列研究方法，分析2015—2018年河北医科大学第四医院肝胆外科行肝细胞癌根治性切除的82例患者的临床病理资料。采用多色荧光免疫组织化学染色的方式，检测患者石蜡切片中PD-L1阳性肿瘤细胞及TIM3阳性肿瘤细胞的数量及占总体肿瘤细胞的比例，采用Survival ROC法确定变量截断值，根据其表达水平将患者分组。依据PD-L1表达量将患者分为PD-L1+（n=21）及PD-L1-（n=61）组，依据TIM3表达量将患者分为TIM3+（n=39）组与TIM3-（n=43）组，依据PD-L1及TIM3两者表达量将患者分为PD-L1+/TIM3+（n=17）、PD-L1+/TIM3-（n=4）、PD-L1-/TIM3+（n=23）以及PD-L1-/TIM3-（n=38）组。采用Kaplan-Meier法结合Log-rank检验分析各组患者之间总体生存时间的差异。结果 Kaplan-Meier法结合Log-rank检验分析显示，PD-L1+组（n=21）与PD-L1-组（n=61）的患者中位生存期（OS）比较，无统计学意义（中位OS=23.3个月与52.0个月，P=0.051），TIM3+组（n=39）与TIM3-组（n=43）的患者中位OS比较，无统计学意义（中位OS=27.6个月与52.9个月，P=0.210），PD-L1+/TIM3+组（n=17）与PD-L1-/TIM3-组（n=38）的患者中位OS比较，无统计学意义（中位OS=18.5个月与53.4个月，P=0.030）。结论 PD-L1及TIM3单一因素的表达差异不足以影响肝细胞癌患者的预后，然而PD-L1及TIM3均呈高表达的患者总体生存显著低于PD-L1及TIM3均呈低表达的患者。这说明PD-L1及TIM3可能在肝癌免疫逃逸的过程中起到协同作用。

关键词: 癌，肝细胞, 肝细胞癌, 预后, 免疫逃逸, 程序性细胞死亡配体1, T细胞免疫球蛋白黏蛋白3

Abstract:

Background

Hepatocellular carcinoma (HCC) is the sixth most common cancer globally, with approximately 415 000 new cases annually in China, accounting for nearly half of the global HCC incidence. HCC can trigger immune escape through various immunosuppressive factors, ultimately leading to tumor progression and metastasis. Programmed cell death ligand 1 (PD-L1) and T cell immunoglobulin mucin-3 (TIM3), recently identified as immunosuppressive factors expressed in HCC, have an unclear relationship with patient prognosis.

Objective

To analyze the impact of PD-L1 and TIM3 expression levels on the prognosis of HCC patients using a retrospective cohort study.

Methods

This retrospective cohort study analyzed the clinicopathological data of 82 HCC patients who underwent radical resection at the Department of Hepatobiliary Surgery, Fourth Hospital of Hebei Medical University, from 2015 to 2018. Multicolor fluorescence immunohistochemistry was used to detect the number and proportion of PD-L1^- positive and TIM3^- positive tumor cells in paraffin-embedded sections. The survival ROC method was applied to determine variable cutoff values, and patients were grouped based on expression levels. Patients were divided into PD-L1⁺ (n=21) and PD-L1^- (n=61) groups based on PD-L1 expression, TIM3⁺ (n=39) and TIM3^- (n=43) groups based on TIM3 expression, and four groups based on combined PD-L1 and TIM3 expression: PD-L1⁺/TIM3⁺ (n=17), PD-L1⁺/TIM3^- (n=4), PD-L1^-/TIM3⁺ (n=23), and PD-L1^-/TIM3^- (n=38). The Kaplan-Meier method with Log-rank test was used to analyze differences in overall survival (OS) among groups.

Results

Kaplan-Meier analysis with Log-rank test showed no statistically significant difference in median OS between the PD-L1⁺ (n=21) and PD-L1^- (n=61) groups (median OS: 23.3 months vs. 52.0 months, P=0.051), nor between the TIM3⁺ (n=39) and TIM3^- (n=43) groups (median OS: 27.6 months vs. 52.9 months, P=0.210). Similarly, no statistically significant difference was observed in median OS between the PD-L1⁺/TIM3⁺ (n=17) and PD-L1^-/TIM3^- (n=38) groups (median OS: 18.5 months vs. 53.4 months, P=0.030).

Conclusion

Differences in the expression of PD-L1 or TIM3 alone are insufficient to impact the prognosis of HCC patients. However, patients with high expression of both PD-L1 and TIM3 exhibit significantly shorter overall survival compared to those with low expression of both markers. This suggests that PD-L1 and TIM3 may play a synergistic role in the immune escape process of HCC.

Key words: Carcinoma, Hepatocellular, Hepatocellular carcinoma, Prognosis, Immune escape, PD-L1, TIM3

中图分类号:

R 730.261

赵思楠,林杉,康希,等. 免疫抑制性因子程序性细胞死亡配体1和T细胞免疫球蛋白黏蛋白3对肝细胞癌患者预后的影响[J]. 中国全科医学, 2026, 29(24): 3461-3465. DOI: 10.12114/j.issn.1007-9572.2023.0543.
ZHAO Sinan,LIN Shan,KANG Xi, et al. Impact of Immune Inhibitory Factors Programmed Cell Death Ligand 1 and T Cell Immunoglobulin Mucin-3 on the Prognosis of Hepatocellular Carcinoma Patients[J]. Chinese General Practice, 2026, 29(24): 3461-3465. DOI: 10.12114/j.issn.1007-9572.2023.0543.

图/表 4

表1 患者基本信息及临床特征（n=82）

Table 1 Basic information and clinical characteristics of patients

项目	构成比[例（%）]	项目	构成比[例（%）]
性别		CNLC分期^a
男	72（87.8）	Ⅰa	27（32.9）
女	10（12.2）	Ⅰb	29（35.4）
肝炎		Ⅱa	6（7.3）
无	3（3.7）	Ⅱb	4（4.9）
乙型肝炎	79（96.3）	Ⅲa	14（17.1）
丙型肝炎	0	Ⅲb	1（1.2）
肝硬化		AFP
有	79（96.3）	≤7.86 ng/mL	24（29.3）
无	3（3.7）	>7.86 ng/mL	58（70.7）
肿瘤数量		糖尿病
单发	73（89.0）	有	10（12.5）
多发	9（11.0）	无	72（87.5）
血管侵犯		饮酒
有	14（17.1）	有	44（53.7）
无	68（82.9）	无	38（46.3）
BCLC分期		吸烟
0	3（3.7）	有	48（58.5）
A	53（64.6）	无	34（41.5）
B	11（13.4）
C	15（18.3）

图1 PD-L1表达水平的多色免疫组化分析及其与患者生存期的相关性注：PD-L1=程序性细胞死亡配体1，DAPI=4'，6-二脒基-2-苯基吲哚；A表示PD-L1-（n=61）和PD-L1+（n=21）两组患者的代表性多色荧光免疫组化切片，B表示PD-L1-组患者与PD-L1+组患者的生存曲线对比。

Figure 1 Multicolor immunohistochemical analysis of PD-L1 expression level and its correlation with patient survival

图2 TIM3表达状态的多色荧光免疫组化分析及其对患者生存预后的影响注：TIM3=T细胞免疫球蛋白黏蛋白3；A表示TIM3-（n=43）和TIM3+（n=39）两组患者的代表性多色荧光免疫组化切片，B表示TIM3-组患者与TIM3+组患者的生存曲线对比。

Figure 2 Multicolor fluorescent immunohistochemical analysis of TIM3 expression status and its influence on patient survival prognosis

图3 PD-L1与TIM3共表达模式的多色荧光免疫组化分析及其对患者生存预后的综合影响注：A表示PD-L1-/TIM3-（n=38）以及PD-L1+/TIM3+（n=17）两组患者的代表性多色荧光免疫组化切片，B表示PD-L1-/TIM3-以及PD-L1+/TIM3+组患者的生存曲线对比。

Figure 3 Multicolor fluorescence immunohistochemical analysis of co-expression pattern between PD-L1 and TIM3 and its comprehensive influence on patient survival prognosis

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免疫抑制性因子程序性细胞死亡配体1和T细胞免疫球蛋白黏蛋白3对肝细胞癌患者预后的影响

Impact of Immune Inhibitory Factors Programmed Cell Death Ligand 1 and T Cell Immunoglobulin Mucin-3 on the Prognosis of Hepatocellular Carcinoma Patients

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