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

周舸; 谢丽平; 林涛发; 卢友光; 王少扬

doi:10.3969/j.issn.1001-5256.2020.11.011

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

DOI: 10.3969/j.issn.1001-5256.2020.11.011

蚌埠医学院福总教学医院(解放军联勤保障部队第九〇〇医院)感染科

基金项目:

院内课题（杰出青年培育专项）（2018Q10）；

详细信息

中图分类号: R735.7
计量
- 文章访问数: 4408
- HTML全文浏览量: 27
- PDF下载量: 75
- 被引次数: 0
出版历程
- 收稿日期: 2019-05-20
- 出版日期: 2020-11-20

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

Department of Infectious Diseases,Fuzhou General Teaching Hospital of Bengbu Medical College & No.900 Hospital of The Joint Service and Security Force of The Chinese People's Liberation Army

Research funding:

摘要

摘要:
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（rs=0.397,P=0.006）。HCC组织中PD-1的表达水平与肿瘤大小（rs=0.480,P=0.001）、门静脉癌栓（rs
- 癌,肝细胞 /
- 程序性细胞死亡受体1 /
- T淋巴细胞免疫球蛋白黏蛋白3 /
- 病理状态,体征和症状 /
- 危险因素
Abstract:
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(rs=0.397,P=0.006).The expression level of PD-1 in HCC tissue was associated with tumor size(rs=0.480,P=0.001),portal vein tumor thrombus(rs=0.307,P=0.038),and TNM stage(rs=0.534,P <0.001),and the expression level of TIM-3 was associated with portal vein tumor thrombus(rs=0.301,P=0.042),degree of pathological differentiation(rs=0.356,P=0.015),and TNM stage(rs=0.416,P=0.004).For the patients with HCC,the 1-,3-,and 5-year overall survival rates were89.1%,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.

HTML全文

参考文献(27)

[1] BRAY F,FERLAY J,SOERJOMATARAM I,et al. Global cancer statistics 2018:GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin,2018,68(6):394-424.

[2] CHEN W,ZHENG R,BAADE PD,et al. Cancer statistics in China,2015[J]. CA Cancer J Clin,2016,66(2):115-132.

[3] RENG ZG. Immunotherapy for hepatocellular carcinoma[J]. J Clin Hepatol,2018,34(7):1371-1373.(in Chinese)任正刚．肝细胞癌的免疫治疗[J]．临床肝胆病杂志，2018,34(7):1371-1373.

[4] BAGHDADI M,JINUSHI M. The impact of the TIM gene family on tumor immunity and immunosuppression[J]. Cell Mol Immunol,2014,11(1):41-48.

[5] SACHDEVA M,CHAWLA YK,ARORA SK. Immunology of hepatocellular carcinoma[J]. World J Hepatol,2015,7(17):2080-2090.

[6] LAN F,LI RM,YANG LY,et al. Anti-tumor immune therapy with programmed death-1 and its ligand inhibitors:research advances[J]. J Int Pharm Res,2016,43(5):813-817.(in Chinese)兰芬，李睿旻，阳凌燕，等．程序性细胞死亡蛋白1及其配体抑制剂抗肿瘤免疫治疗进展[J]．国际药学研究杂志，2016,43(5):813-817.

[7] JOYCE JA,FEARON DT. T cell exclusion,immune privilege,and the tumor microenvironment[J]. Science,2015,348(6230):74-80.

[8] MONNEY L,SABATOS CA,GAGLIA JL,et al. Th1-specific cell surface protein Tim-3 regulates macrophage activation and severity of an autoimmune disease[J]. Nature,2002,415(6871):536-541.

[9] ANDERSON AC,ANDERSON DE,BREGOLI L,et al. Promotion of tissue inflammation by the immune receptor Tim-3 expressed on innate immune cells[J]. Science,2007,318(5853):1141-1143.

[10] JU Y,HOU N,MENG J,et al. T cell immunoglobulin-and mucin-domain-containing molecule-3(Tim-3)mediates natural killer cell suppression in chronic hepatitis B[J]. J Hepatol,2010,52(3):322-329.

[11] WU W,SHI Y,LI S,et al. Blockade of Tim-3 signaling restores the virus-specific CD8+T-cell response in patients with chronic hepatitis B[J]. Eur J Immunol,2012,42(5):1180-1191.

[12] ANDERSON AC. Tim-3,a negative regulator of anti-tumor immunity[J]. Curr Opin Immunol,2012,24(2):213-216.

[13] PATEL J,BOZEMAN EN,SELVARAJ P. Taming dendritic cells with TIM-3:Another immunosuppressive strategy used by tumors[J]. Immunotherapy,2012,4(12):1795-1798.

[14] HARDING JJ,EL DIKA I,ABOU-ALFA GK. Immunotherapy in hepatocellular carcinoma:Primed to make a difference?[J]. Cancer,2016,122(3):367-377.

[15] JI M,LIU Y,LI Q,et al. PD-1/PD-L1 pathway in nonsmall-cell lung cancer and its relation with EGFR mutation[J]. J Transl Med,2015,13:5.

[16] FREEMAN-KELLER M,WEBER JS. Anti-programmed death receptor 1 immunotherapy in melanoma:Rationale,evidence and clinical potential[J]. Ther Adv Med Oncol,2015,7(1):12-21.

[17] HUANG RY,EPPOLITO C,LELE S,et al. LAG3 and PD1 co-inhibitory molecules collaborate to limit CD8+T cell signaling and dampen antitumor immunity in a murine ovarian cancer model[J]. Oncotarget,2015,6(29):27359-27377.

[18] SHINOHARA T,TANIWAKI M,ISHIDA Y,et al. Structure and chromosomal localization of the human PD-1 gene(PDCD1)[J]. Genomics,1994,23(3):704-706.

[19] FRANCISCO LM,SAGE PT,SHARPE AH. The PD-1 pathway in tolerance and autoimmunity[J]. Immunol Rev,2010,236:219-242.

[20] LIU LX,CAI W. Current situation and prospect of immunotherapy for hepatocellular carcinoma[J]. Chin J Dig Surg,2020,19(2):119-122.(in Chinese)刘连新，蔡伟．肝细胞癌免疫治疗的现状和展望[J]．中华消化外科杂志，2020,19(2):119-122.

[21] FIFE BT,PAUKEN KE,EAGAR TN,et al. Interactions between PD-1 and PD-L1 promote tolerance by blocking the TCR-induced stop signal[J]. Nat Immunol,2009,10(11):1185-1192.

[22] ZHU C,ANDERSON AC,KUCHROO VK. TIM-3 and its regulatory role in immune responses[J]. Curr Top Microbiol Immunol,2011,350:1-15.

[23] SOLINAS G,GERMANO G,MANTOVANI A,et al. Tumorassociated macrophages(TAM)as major players of the cancer-related inflammation[J]. J Leukoc Biol,2009,86(5):1065-1073.

[24] BISWAS SK,MANTOVANI A. Macrophage plasticity and interaction with lymphocyte subsets:Cancer as a paradigm[J].Nat Immunol,2010,11(10):889-896.

[25] MASSAGUE J. TGFbeta in cancer[J]. Cell,2008,134(2):215-230.

[26] YAN WJ. TGFβenhanced Tim-3 expression on macrophages fosters M2-like alternative activation contributing to HCC[D].Jinan:Shandong University,2014.(in Chinese)阎文江．Tim-3在肿瘤相关巨噬细胞极化及肝细胞肝癌进展中的作用及机制研究[D]．济南:山东大学，2014.

[27] LI Z,LI N,LI F,et al. Immune checkpoint proteins PD-1 and TIM-3 are both highly expressed in liver tissues and correlate with their gene polymorphisms in patients with HBV-related hepatocellular carcinoma[J]. Pubmed, 2016, 95(52):e5749.

施引文献

资源附件(0)

访问统计