免疫治疗后肝细胞癌组织中CD69^(+)T细胞的空间分布变化及意义  

Spatial distribution changes of CD69^(+)T in hepatocellular carcinoma after immunotherapy and its significance

作　　者：马炬 朱颖 徐洋 王文森 朱新燕 李世朋 王连才 李德宇 Ma Ju;Zhu Ying;Xu Yang;Wang Wensen;Zhu Xinyan;Li Shipeng;Wang Liancai;Li Deyu(Department of Hepatobiliary and Pancreatic Surgery,People's Hospital of Zhengzhou University,Zhengzhou 450003,China;Department of Hepatobiliary and Pancreatic Surgery,the First Affiliated Hospital of Zhengzhou University,Zhengzhou 450003,China;Department of Hepatobiliary and Pancreatic Surgery,People's Hospital of Henan University,Zhengzhou 450003,China)

机构地区：[1]郑州大学人民医院肝胆胰腺外科,郑州450003 [2]郑州大学第一附属医院肝胆胰腺外科,郑州450003 [3]河南大学人民医院肝胆胰腺外科,郑州450003

出　　处：《中华肝胆外科杂志》2025年第3期202-207,共6页Chinese Journal of Hepatobiliary Surgery

基　　金：河南省科技攻关项目(202102310126)。

摘　　要：目的分析免疫治疗后肝细胞患者癌组织中CD69^(+)T细胞变化及与肿瘤组织浸润性免疫细胞的关系。方法收集2023年7月至2024年7月就诊于郑州大学人民医院和郑州大学第一附属医院肝胆胰腺外科的12例肝细胞癌患者癌组织、癌旁正常组织以及二者交界区组织,其中男性10例,女性2例,年龄(58.5±5.6)岁。12例患者中有6例直接行根治性手术,术前未接受过任何治疗,纳入对照组(n=6),接受免疫治疗后行根治性手术的6例患者纳入免疫治疗组(n=6)。MRI或CT扫描测量免疫治疗组肿瘤最大径和肿瘤体积。免疫组化和免疫荧光检测CD8^(+)CD69^(+)T、CD4^(+)CD69^(+)T、程序性死亡受体1(PD1)等表达和分布情况。计算目标细胞周围其他免疫细胞数量记做有效评分,同时测量细胞间距离,评估细胞间相互作用。结果6例患者免疫治疗后肿瘤最大径和肿瘤体积均低于治疗前,差异均有统计学意义(均P<0.05)。免疫治疗组癌组织中PD1^(+)细胞密度为36.6(25.9,55.9)个/mm^(2),少于对照组的53.9(38.3,84.5)个/mm^(2),差异有统计学意义(Z=-2.66,P=0.008)。对照组3个区域CD8^(+)CD69^(+)T细胞与CD8^(+)PD1^(+)T细胞、CD8^(+)PD1^(+)CD103^(+)T细胞数量呈正相关,相关系数分别为0.42、0.40(P=0.001、0.002)。免疫治疗组3个区域CD8^(+)CD69^(+)T细胞与CD8^(+)PD1^(+)T、CD4^(+)CD103^(+)T、CD4^(+)PD1^(+)CD103^(+)T、CD8^(+)PD1^(+)CD103^(+)T细胞等免疫细胞的有效评分低于对照组,差异均有统计学意义(均P<0.05)。对照组交界区内CD8^(+)CD69^(+)T与CD4^(+)CD69^(+)CD103^(+)T细胞的距离相较于免疫治疗组更近,差异有统计学意义(t=2.67,P=0.009)。结论肝细胞癌患者免疫治疗后癌组织PD-1^(+)细胞减少,CD8^(+)CD69^(+)T细胞周围的免疫细胞减少,这种变化与CD8^(+)CD103^(+)T细胞距离变远有关。Objective To investigate changes in the density and spatial distribution of CD69^(+)T cells within hepatocellular carcinoma tissues following immune checkpoint blockade(ICB)therapy,and to explore their correlation with tumor infiltrating immune cell.Methods Tumor specimens were collected from 12 patients with hepatocellular carcinoma who were admitted to the Department of Hepatobiliary and Pancreatic Surgery of People's Hospital of Zhengzhou University and the First Affiliated Hospital of Zhengzhou University from July 2023 to July 2024.There were 10 males and 2 females,aged(58.5±5.6)years.Of the 12 patients,6 cases underwent radical surgery directly and 6 underwent radical surgery after immunotherapy.The maximum tumor diameter and tumor volume of the immunotherapy group were measured by imaging.The density and distribution of immune cells such as CD8^(+)CD69^(+)T,CD4^(+)CD69^(+)T and programmed death-1(PD-1)were detected by immunohistochemistry and immunofluorescence.The number of immune cells around the target cells was calculated to evaluate the effective score,and the intercellular distance was measured to evaluate the intercellular interaction.Results The maximum tumor diameter and tumor volume of 6 patients after immunotherapy were lower than before treatment,and the differences were statistically significant(all P<0.05).The density of PD1^(+)cells in the immunotherapy group was 36.6(25.9,55.9)cells/mm 2,which was less than that in the control group 53.9(38.3,84.5)cells/mm 2,and the difference was statistically significant(Z=-2.66,P=0.008).In the control group,the number of CD8^(+)CD69^(+)T cells was positively correlated with CD8^(+)PD1^(+)T cells and CD8^(+)PD1^(+)CD103^(+)T cells,and the correlation coefficients were 0.42 and 0.40,respectively(P=0.001,0.002).The effective scores of CD8^(+)CD69^(+)T cells and CD8^(+)PD1^(+)T,CD4^(+)CD103^(+)T,CD4^(+)PD1^(+)CD103^(+)T and CD8^(+)PD1^(+)CD103^(+)T cells in the above three areas in the immunotherapy group were lower than those in the control group,with stat

关 键 词：癌 肝细胞 CD69^(+)T细胞 免疫治疗 空间分布 

分 类 号：R735.7[医药卫生—肿瘤]