肝细胞癌组织中程序性死亡受体1和T淋巴细胞免疫球蛋白黏蛋白3的表达及意义

Expression and significance of programmed death-1 and T-cell immunoglobulin-and mucin domain-3-containing molecule 3 in hepatocellular carcinoma

目的探讨程序性死亡受体1(PD-1)和T淋巴细胞免疫球蛋白黏蛋白3(TIM-3)在肝细胞癌(HCC)中的表达情况及其临床意义。方法收集2013年1月-2015年12月于中国人民解放军联勤保障部队第九〇〇医院接受手术治疗的46例HCC患者的癌组织及癌旁组织(距癌缘> 1 cm)蜡块采用免疫组化法检测组织中PD-1和TIM-3的表达,分析两者的表达情况,及两者与临床病理特征和预后的关系。配对等级资料的比较采用Wilcoxon检验,等级资料的相关性分析采用Spearman法,采用KaplanMeier法进行生存分析,log-rank检验比较组间生存率差异,采用Cox回归分析模型进行多因素分析。结果 HCC组织中PD-1、TIM-3的表达水平均高于癌旁组织(P值均<0.05),PD-1主要定位于淋巴细胞中,TIM-3主要定位于肿瘤相关巨噬细胞中。HCC组织中PD-1和TIM-3的表达呈正相关(r_s=0.397,P=0.006)。HCC组织中PD-1的表达水平与肿瘤大小(r_s=0.480,P=0.001)、门静脉癌栓(r_s=0.307,P=0.038)、TNM分期(r_s=0.534,P<0.001)有关,TIM-3的表达水平与门静脉癌栓(r_s=0.301,P=0.042)、病理分化程度(r_s=0.356,P=0.015)和TNM分期(r_s=0.416,P=0.004)有关。所有HCC患者的1、3及5年总生存率分别为89.1%、56.5%和34.4%;1、3及5年无病生存率分别为52.2%、21.7%和10.9%。多因素分析显示,病理分化程度(HR=4.723,95%CI:1.618~7.684,P=0.001)、肿瘤大小(HR=3.234,95%CI:1.327~7.883,P=0.010)、TNM分期(HR=3.254,95%CI:1.076~9.835,P=0.037)、TIM-3的表达水平(HR=0.572,95%CI:0.329~0.995,P=0.048)均是HCC患者总生存期的独立预后因素;病理分化程度(HR=2.945,95%CI:1.527~5.682,P=0.001)、TNM分期(HR=2.074,95%CI:1.259~9.793,P=0.016)均是HCC患者无病生存期的独立预后因素。结论 HCC组织中同时存在着PD-1和TIM-3的高表达,PD-1、TIM-3可能参与了HCC患者的疾病进展和不良预后。

Objective To investigate the expression and clinical significance of programmed death-1(PD-1)and T-cell immunoglobulin-and mucin domain-3-containing molecule 3(TIM-3)in hepatocellular carcinoma(HCC).Methods The paraffin blocks of HCC tissue and adjacent tissue(>1 cm from the tumor margin)were collected from 46 patients with HCC who underwent surgical treatment in No.900 Hospital of The Joint Service and Security Force of The Chinese People’s Liberation Army from January 2013 to December 2015.Immunohistochemistry was used to measure the expression of PD-1 and TIM-3,and their association with clinicopathological features and prognosis was analyzed.The Wilcoxon test was used for comparison of paired ranked data,and a Spearman correlation analysis was used to investigate the correlation between ranked data;the Kaplan-Meier method was used for survival analysis,and the log-rank test was used for comparison of survival rates between groups;the Cox regression model was used to perform a multivariate analysis.Results The expression levels of PD-1 and TIM-3 in HCC tissue were higher than those in adjacent tissue(both P<0.05).PD-1 was mainly localized in lymphocytes and TIM-3 was mainly localized in tumor-associated macrophages.The expression of PD-1 was positively correlated with that of TIM-3 in HCC tissue(r s=0.397,P=0.006).The expression level of PD-1 in HCC tissue was associated with tumor size(r s=0.480,P=0.001),portal vein tumor thrombus(r s=0.307,P=0.038),and TNM stage(r s=0.534,P<0.001),and the expression level of TIM-3 was associated with portal vein tumor thrombus(r s=0.301,P=0.042),degree of pathological differentiation(r s=0.356,P=0.015),and TNM stage(r s=0.416,P=0.004).For the patients with HCC,the 1-,3-,and 5-year overall survival rates were 89.1%,56.5%,and 34.4%,respectively,and the 1-,3-,and 5-year disease-free survival rates were 52.2%,21.7%,and 10.9%,respectively.The multivariate analysis showed that degree of pathological differentiation(hazard ratio[HR]=4.723,95%confidence interval[CI]:1.618-7.684,P=0.001),tumor size(HR=3.234,95%CI:1.327-7.883,P=0.010),TNM stage(HR=3.254,95%CI:1.076-9.835,P=0.037),and expression level of TIM-3(HR=0.572,95%CI:0.329-0.995,P=0.048)were independent prognostic factors for the overall survival of HCC patients,and degree of pathological differentiation(HR=2.945,95%CI:1.527-5.682,P=0.001)and TNM stage(HR=2.074,95%CI:1.259-9.793,P=0.016)were independent prognostic factors for the disease-free survival of HCC patients.Conclusion High expression levels of both PD-1 and TIM-3 are observed in HCC tissue,and PD-1 and TIM-3 may be involved in the progression and poor prognosis of HCC patients.