核纤层蛋白B2在胃癌中高表达并调节胃癌的免疫微环境

Lamin B2 is highly expressed in gastric cancer and regulates the immune microenvironment

目的:研究核纤层蛋白B2(LMNB2)在胃癌患者中的表达特征及其与临床预后、临床病理特征相关性,并探讨LMNB2表达对胃癌免疫微环境的影响。方法:下载UCSC数据库中经统一标准化的泛癌数据集,对其中19131例癌旁正常组织及60499例肿瘤组织中LMNB2的表达情况进行分析。收集自2014年至2016年间在温州医科大学附属第一医院行胃癌根治性切除术的142例胃癌组织及28例配对癌旁正常组织,免疫组化技术检测127例胃癌组织及28对配对癌旁组织中LMNB2的差异表达情况,并结合临床信息,对LMNB2表达情况与患者预后、临床病理特征之间的关系进行分析。采用ESTIMATE等算法分析LMNB2表达水平对胃癌组织中的基质、免疫细胞浸润等的影响;分析胃癌组织中不同免疫细胞的浸润情况及肿瘤突变负荷(TMB)、微卫星不稳定性(MSI)、细胞程序性死亡-配体1(PD-L1)与LMNB2表达水平之间的相关性,并通过基于免疫组化技术进行的评分,对临床组织样本进一步验证分析。结果:LMNB2在胃癌组织中表达上调,与患者的不良预后、更差的TNM分期等临床病理特征相关性。ESTIMATE分析显示,LMNB2的表达与免疫评分(r=-0.202,P<0.001)、基质评分(r=-0.272,P<0.001)、ESTIMATE评分(r=-0.251,P<0.001)呈负相关。免疫细胞的浸润情况分析发现,LMNB2表达与M1型巨噬细胞(r=0.322,P<0.001)、NK细胞(r=0.423,P<0.001)、中性粒细胞(r=0.307,P<0.001)浸润呈正相关。免疫组化对组织芯片进一步分析显示LMNB2高表达组拥有更高的CD4、CD56评分(均P<0.05),而其CD8、CD163评分则更低(均P<0.05)。LMNB2的表达水平与胃癌中TMB评分(r=0.343,P<0.001)及MSI评分(r=0.221,P<0.001)呈正相关,且LMNB2高表达组的PD-L1表达水平上调(P<0.05)。结论:LMNB2在胃癌中的表达上调,调节胃癌中的免疫微环境,可能是潜在的胃癌诊断标志物及评价胃癌病人免疫检查点抑制剂疗效的指标。

Objective:To investigate the expression characteristics of lamin B2(LMNB2)in patients with gastric cancer and its correlation with clinical prognosis and clinicopathological features,to explore the effect of LMNB2 on immune microenvironment of gastric cancer.Methods:A unified and standardized pan-cancer dataset was downloaded from UCSC database to analyze the expression of LMNB2 in 19131 normal tissues adjacent to cancer and 60499 tumor tissues.A total of 142 gastric cancer tissues and 28 paracancer normal tissues that underwent radical resection of gastric cancer in the First Affiliated Hospital of Wenzhou Medical University from 2014 to 2016 were collected.The differential expression of LMNB2 in 127 gastric cancer tissues and 28 paracancerous tissues was detected by immunohistochemistry.The relationship between the expression of LMNB2 and the prognosis and clinicopathological features of patients were analyzed combined with clinical information.The ESTIMATE algorithm was used to analyze the effect of LMNB2 expression level on matrix and immune cell infiltration in gastric cancer tissues.The infiltration of different immune cells in gastric cancer tissues and the correlation between tumor mutation burden(TMB),microsatellite instability(MSI),programmed cell death 1 ligand 1(PD-L1)and LMNB2 expression levels were analyzed,and the clinical tissue samples were further verified and analyzed.Results:The expression of LMNB2 was up-regulated in gastric cancer tissues,which was associated with poor prognosis and worse TNM stage of patients.The ESTIMATE analysis showed that the expression of LMNB2 was negatively correlated with immune score(r=-0.202,P<0.001),matrix score(r=-0.272,P<0.001)and ESTIMATE score(r=-0.251,P<0.001).Analysis of the infiltration of immune cells showed that the expression of LMNB2 was significantly positively correlated with the infiltration of M1 macrophages(r=0.322,P<0.001),NK cells(r=0.423,P<0.001)and neutrophils(r=0.307,P<0.001).Furthermore,immunohistochemical analysis of tissue chips showed that the high expression group of LMNB2 had higher CD4(P<0.05)and CD56(P<0.05)scores,but lower CD8(P<0.05)and CD163(P<0.01)scores.The expression level of LMNB2 was significantly positively correlated with TMB scores(r=0.343,P<0.001)and MSI scores(r=0.221,P<0.001)in gastric cancer,and the expression of PD-L1 in the high expression group of LMNB2 was up-regulated(P<0.05).Conclusion:The up-regulated expression of LMNB2 in gastric cancer regulates the immune microenvironment in gastric cancer,which may be a potential diagnostic marker for gastric cancer and an indicator to evaluate the efficacy of immune checkpoint inhibitors in patients with gastric cancer.