PD-1、Tim-3、BTLA蛋白在食管鳞癌组织中的表达及其与预后的关系

Expression of PD-1,Tim-3 and BTLA Protein in Esophageal Squamous Cell Carcinoma and Their Relationship with Prognosis

目的探讨食管鳞状细胞癌(简称鳞癌)组织中程序性细胞死亡受体1(PD-1)、T细胞免疫球蛋白黏蛋白分子-3(Tim-3)、B和T淋巴细胞弱化因子(BTLA)蛋白的表达情况及其与预后的关系。方法选取2014年9月至2015年9月在新乡医学院第一附属医院胸外科一病区行手术治疗的96例食管鳞癌患者作为研究对象。采用免疫组织化学检测食管鳞癌组织中PD-1、Tim-3和BTLA蛋白的表达,分析其与临床病理特征的关系,并采用Spearman法分析三者的相关性。采用单因素和多因素Cox风险比例模型分析影响食管鳞癌患者预后的因素。结果96例食管鳞癌患者中,PD-1蛋白的阳性表达率为52.08%(50/96),Tim-3蛋白的阳性表达率为73.96%(71/96),BTLA蛋白的阳性表达率为64.58%(62/96)。浸润食管外膜PD-1、Tim-3、BTLA蛋白的阳性表达率高于浸润黏膜+肌层[61.43%(43/70)比26.92%(7/26)、80.00%(56/70)比57.69%(15/26)、72.86%(51/70)比42.31%(11/26)](P<0.05或P<0.01);有淋巴结转移PD-1、Tim-3、BTLA蛋白的阳性表达率高于无淋巴结转移[70.59%(36/51)比31.11%(14/45)、84.31%(43/51)比62.22%(28/45)、80.39%(41/51)比46.67%(21/45)](P<0.05或P<0.01)。Spearman相关分析显示,PD-1蛋白的阳性表达与Tim-3、BTLA蛋白的阳性表达呈正相关(r=0.401,P<0.001;r=0.467,P<0.001),Tim-3蛋白的阳性表达与BTLA蛋白的阳性表达呈正相关(r=0.627,P<0.001)。PD-1、Tim-3和BTLA蛋白阳性表达食管鳞癌患者的5年总生存率分别为8.00%、14.30%、14.50%,PD-1、Tim-3和BTLA蛋白阴性表达食管鳞癌患者5年总生存率分别为43.50%、40.50%、43.90%。PD-1、Tim-3和BTLA蛋白阴性表达食管鳞癌患者的中位生存时间长于阳性表达患者(χ^(2)=19.516,P<0.001;χ^(2)=8.108,P=0.004;χ^(2)=8.384,P=0.004)。Cox模型单因素、多因素分析结果显示,PD-1、Tim-3和BTLA蛋白是影响食管鳞癌患者预后的独立危险因素(P<0.01)。结论PD-1、Tim-3和BTLA蛋白在食管鳞癌组织中的表达水平与浸润深度、淋巴结转移显著相关,且影响患者预后,有望为食管鳞癌的治疗提供可靠的靶点。

Objective To investigate the expression of programmed cell death receptor 1(PD-1),T-cell immunoglobulin and mucin domain protein-3(Tim-3)and B and T lymphocyte attenuator(BTLA)in esophageal squamous cell carcinoma(ESCC)and their relationship with the prognosis.Methods A total of 96 ESCC patients who received surgical treatment in the Department of Thoracic Surgery No.1 Ward of the First Affiliated Hospital of Xinxiang Medical University from Sep.2014 to Sep.2015 were included.Immunohistochemistry method was used to detect the expression of PD-1,Tim-3 and BTLA in esophageal squamous cell carcinoma tissue,and the relationship between them and the clinicopathological features was analyzed.Spearman method was used to analyze the correlation between the three proteins.Univariate and multivariate Cox proportional hazards models were used to analyze the factors affecting the prognosis of the ESCC patients.Results Among the 96 ESCC patients,the positive expression rate of PD-1 protein was 52.08%(50/96),of Tim-3 protein was 73.96%(71/96),and of BTLA protein was 64.58%(62/96).The positive expression rate of PD-1,Tim-3 and BTLA proteins in the infiltrating esophageal adventitia was higher than that in the infiltrating mucosa+muscularis[61.43%(43/70)vs 26.92%(7/26),80.00%(56/70)vs 57.69%(15/26),72.86%(51/70)vs 42.31%(11/26)](P<0.05 or P<0.01);the positive expression rates of PD-1,Tim-3 and BTLA proteins with lymph node metastasis were higher than those without lymph node metastasis[70.59%(36/51)vs 31.11%(14/45),84.31%(43/51)vs 62.22%(28/45),80.39%(41/51)vs 46.67%(21/45)](P<0.05 or P<0.01).Spearman correlation analysis showed that the positive expression of PD-1 protein was positively correlated with the positive expression of Tim-3 and BTLA protein(r=0.401,P<0.001;r=0.467,P<0.001).The positive expression of Tim-3 and BTLA protein was positively correlated(r=0.627,P<0.001).The 5-year overall survival rates of ESCC patients with positive expression of PD-1,Tim-3 and BTLA proteins were 8.00%,14.30%and 14.50%,respectively.The 5-year overall survival rates of ESCC patients with negative expression of PD-1,Tim-3 and BTLA proteins were 43.50%,40.50%,and 43.90%.The median survival time of the ESCC patients with negative expression of PD-1,Tim-3 and BTLA proteins was longer than that of patients with positive expression(χ^(2)=19.516,P<0.001;χ^(2)=8.108,P=0.004;χ^(2)=8.384,P=0.004).Univariate and multivariate analysis of Cox model showed that PD-1,Tim-3 and BTLA proteins were independent risk factors affecting the prognosis of ESCC patients(P<0.01).Conclusion The expression levels of PD-1,Tim-3 and BTLA proteins in ESCC are significantly correlated with the depth of invasion and lymph node metastasis,and affect the prognosis of the patients,which are expected to provide reliable targets for the treatment of ESCC.