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

doi:10.19401/j.cnki.1007-3639.2019.05.005

中国癌症杂志 ›› 2019, Vol. 29 ›› Issue (5): 352-361.doi: 10.19401/j.cnki.1007-3639.2019.05.005

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

马家强^1,2，曹春梅³，Shyamal Goswami ²，陈　沁¹，高　强⁴，张晓明²

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

出版日期:2019-05-30 发布日期:2019-06-03
通信作者: 张晓明 E-mail: xmzhang@ips.ac.cn
基金资助:
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）和创新交叉团队项目；国家自然科学基金（81602488）。

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

MA Jiaqiang^1,2, CAO Chunmei³, Shyamal Goswami², CHEN Qin¹, GAO qiang⁴, ZHANG Xiaoming²

1. School of Life Sciences, Shanghai University, Shanghai 200444, China; 2. Institute Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031, China; 3. Cancer Institute, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; 4. Department of Liver Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China

Published:2019-05-30 Online:2019-06-03
Contact: ZHANG Xiaoming E-mail: xmzhang@ips.ac.cn

摘要/Abstract

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Kaplan-Meier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。

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

Abstract: 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 (mIHC) 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.

Key words: Hepatocellular carcinoma, Inducible costimulator, Multiplex immunohistochemistry, Prognosis

马家强，曹春梅，Shyamal Goswami,陈　沁，高　强，张晓明. 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[J]. 中国癌症杂志, 2019, 29(5): 352-361.

MA Jiaqiang, CAO Chunmei, Shyamal Goswami, CHEN Qin, GAO qiang, ZHANG Xiaoming. Detection of ICOS⁺T cells by multiplex immunohistochemistry in tumor tissue and its clinical significance in hepatocellular carcinoma[J]. China Oncology, 2019, 29(5): 352-361.

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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

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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

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