肝细胞癌组织ICOS^+T细胞的多重免疫组织化学检测及其预后价值研究  

Detection of ICOS^+ T cells by multiplex immunohistochemistry in tumor tissue and its clinical significance in hepatocellular carcinoma

作　　者：马家强 曹春梅 Shyamal Goswami 陈沁[1] 高强 张晓明[2] MA Jiaqiang;CAO Chunmei;CHEN Qin;GAO qiang;ZHANG Xiaoming(School of Life Sciences, Shanghai University, Shanghai 200444, China;Institute Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031, China;Cancer Institute, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China;Department of Liver Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China)

机构地区：[1]上海大学生命科学学院,上海200444 [2]中国科学院上海巴斯德研究所,上海200031 [3]复旦大学附属肿瘤医院肿瘤研究所,复旦大学上海医学院肿瘤学系,上海200032 [4]复旦大学附属中山医院肝脏外科,上海200032

出　　处：《中国癌症杂志》2019年第5期352-361,共10页China Oncology

基　　金：中国科学院战略性先导科技专项(XDB29030302);前沿科学重点研究计划前沿科学重点项目(QYZDB-SSW-SMC036);创新交叉团队项目;国家自然科学基金(81602488)

摘　　要：背景与目的:诱导共刺激分子(inducible costimulator,ICOS)属于B7-CD28免疫球蛋白超家族成员,表达于活化T细胞表面,在T细胞的激活和免疫应答中发挥重要作用;但目前对于ICOS及ICOS^+T细胞在肝细胞癌(hepatocellular carcinoma,HCC)肿瘤组织中的表达及其意义尚不清楚。该研究旨在测定ICOS、ICOS^+T细胞在HCC患者肿瘤组织中的表达情况并探讨其预后价值。方法:应用组织芯片(tissue microarrays,TMAs)和多重免疫组织化学技术(multiplex immunohistochemistry,mIHC)检测2006-2007年在复旦大学附属中山医院接受手术治疗的358例原发性HCC患者肿瘤组织和癌旁组织中ICOS^+细胞、ICOS^+CD4^+及ICOS^+CD8^+T细胞的浸润密度和ICOS^+细胞占CD4^+、CD8^+T细胞的百分比。应用KaplanMeier法和多因素COX回归模型分析上述指标对患者预后的影响。结果:与癌旁组织相比,ICOS^+细胞和ICOS^+CD4^+T细胞在肿瘤组织中浸润数量显著增加(P<0.000 1和P=0.009 1),而ICOS^+CD8^+T细胞则呈相反的降低趋势(P=0.033);在肿瘤中,ICOS^+CD4^+T细胞的浸润程度显著高于ICOS^+CD8^+T细胞。此外,ICOS^+CD4^+和ICOS^+CD8^+T细胞占各自T细胞亚群的百分比在肿瘤组织中均显著增加(P均<0.000 1)。预后分析发现,肿瘤组织中ICOS^+细胞、ICOS^+CD4^+及ICOS^+CD8^+T细胞浸润高的患者总生存期(overall survival,OS)更长,多因素分析证实上述指标是HCC的独立预后良好因素。结论:ICOS在HCC患者的肿瘤组织中高表达,且ICOS^+细胞、ICOS^+CD4^+及ICOS^+CD8^+T细胞是OS的独立预后良好因素,提示上述指标可作为新的HCC预后免疫标志物。Background and purpose: Inducible costimulator(ICOS) is a member of B7-CD28 immunoglobulin superfamily and expressed on the surface of activated T cells, which plays an important role in T cell activation and effector functions. However, the expression pattern and the significance of ICOS and ICOS^+ T cells in tumor tissue of hepatocellular carcinoma(HCC) are not defined.To this end, the current study was planned to quantitatively detect the expression of ICOS and ICOS^+ T cells in the tumor tissue of HCC patients and evaluate their clinical significance. Methods: Tissue microarrays(TMAs) and multiplex immunohistochemistry(m IHC) were used to detect the expression levels of ICOS^+ cells, ICOS^+CD4^+ and ICOS^+CD8^+ T cells in tumor and paracancerous tissues from HCC patients who received surgical treatment in Zhongshan Hospital, Fudan University from 2006 to 2007(n=358).The clinical prognosis was evaluated by Kaplan-Meier analysis and COX regression analysis. Results: The densities of infiltrating ICOS^+ and ICOS^+CD4^+ T cells were significantly higher in tumor tissue than in paracancerous tissue(P<0.000 1 and P=0.009 1). By contrast, the density of ICOS^+CD8^+ T cells was significantly lower in tumor tissue than in paracancerous tissue(P=0.033). Within the tumor tissue, the density of ICOS^+CD4^+ T cells was significantly higher compared with ICOS^+CD8^+ T cells(P<0.000 1). Moreover,the frequencies of ICOS^+CD4^+ and ICOS^+CD8^+ T cells in tumor tissue were significantly higher compared with their counterparts in paracancerous tissue(P<0.000 1). Multivariate COX regression analysis identified that ICOS^+ cells, ICOS^+CD4^+ and ICOS^+CD8^+ T cells were independent favorable prognostic indices for overall survival(OS). Conclusion: Tumor infiltrating ICOS^+ cells are greatly elevated in the tumor tissue of HCC, and their abundance is associated with prolonged OS. Thus, ICOS^+ cells, ICOS^+CD4^+ and ICOS^+CD8^+ T cells might be used as novel prognostic immune biomarkers for HCC.

关 键 词：肝细胞癌 诱导共刺激分子 多重免疫组织化学技术 预后 

分 类 号：R735.7[医药卫生—肿瘤]