胃癌组织细胞程序性死亡配体1表达情况和CD_(8)^(+)肿瘤浸润T淋巴细胞密度及其与患者临床病理特征和预后的关系研究

Expression of Programmed Death Ligand 1 and Density of CD_(8)^(+) Tumor-infiltrating T-lymphocytes in Gastric Cancer Tissues and Their Relationship with Clinicopathological Characteristics and Prognosis of Patients with Gastric Cancer

背景目前,胃癌组织细胞程序性死亡配体1(PD-L1)表达情况和CD_(8)^(+)肿瘤浸润T淋巴细胞(TILs)密度是否可作为胃癌患者预后的评估指标尚不明确。目的分析胃癌组织PD-L1表达情况、CD_(8)^(+)TILs密度及其与患者临床病理特征和预后的关系。方法选择2016年1月至2018年3月在南阳市第一人民医院行手术治疗的胃癌患者125例,采用实时荧光定量反转录聚合酶链反应检测其胃癌组织PD-L1 mRNA相对表达量,采用免疫组化方法检测其胃癌组织CD_(8)^(+)TILs密度。分析胃癌组织PD-L1 mRNA相对表达量、CD_(8)^(+)TILs密度与患者临床病理特征的关系;胃癌组织PD-L1 mRNA相对表达量与CD_(8)^(+)TILs密度的相关性分析采用Pearson相关分析;通过电话随访至术后36个月,以患者死亡或失访为终点事件,绘制Kaplan-Meier曲线以进行生存分析;胃癌患者预后的影响因素分析采用单因素和多因素Cox回归分析。结果所有患者胃癌组织平均PD-L1 mRNA相对表达量为3.1,癌巢内平均CD_(8)^(+)TILs数量为36个,最终归为低水平组73例(PD-L1 mRNA相对表达量<3.1)和高水平组52例(PD-L1 mRNA相对表达量≥3.1),低密度组55例(CD_(8)^(+)TILs数量<36个)和高密度组70例(CD_(8)^(+)TILs≥36个)。低水平组与高水平组患者淋巴结转移、脉管侵犯、腹膜转移情况比较,差异有统计学意义(P<0.05);低密度组与高密度组患者浸润深度、淋巴结转移、脉管侵犯、腹膜转移情况比较,差异有统计学意义(P<0.05)。Pearson相关分析结果显示,胃癌组织PD-L1 mRNA相对表达量与CD_(8)^(+)TILs密度呈负相关(r=-0.412,P<0.001)。中位随访时间为36.0个月,125例患者中预后不良37例,预后良好88例;低水平组与高水平组、低密度组与高密度组患者Kaplan-Meier曲线比较,差异均有统计学意义(P<0.05)。多因素Cox回归分析结果显示,高水平PD-L1 mRNA〔HR=3.021,95%CI(1.632,5.045)〕、低密度CD_(8)^(+)TILs〔HR=2.158,95%CI(1.854,4.632)〕为胃癌患者预后不良的独立危险因素(P<0.05)。结论高水平PD-L1 mRNA、低密度CD_(8)^(+)TILs均是胃癌患者预后不良的独立危险因素,有望成为胃癌患者预后不良的生物标志物。

Background At present,whether the expression of programmed death ligand 1(PD-L1)and the density of CD_(8)^(+) tumor-infiltrating T lymphocytes(TILs)in gastric cancer tissue can be used as prognostic indicators for gastric cancer patients has been still unclear.Objective To analyze the expression of PD-L1 and density of CD8+TILs in gastric cancer tissues and their relations with clinicopathological characteristics and prognosis of patients with gastric cancer.Methods A total of 125 gastric cancer patients underwent surgical treatment in Nanyang First People’s Hospital from January 2016 to March 2018 were selected,and the expression level of PD-L1 mRNA in gastric cancer tissue was detected by real-time fluorescence quantitative polymerase chain reaction,the density of CD_(8)^(+) TILs in gastric cancer tissue was detected by immunohistochemical methods.The relations of the relative expression quantity of PD-L1 mRNA and the density of CD_(8)^(+) TILs in gastric cancer tissue with the clinicopathological characteristics of patients with gastric cancer was analyzed;the correlation between the relative expression quantity of PD-L1 mRNA and the density of CD_(8)^(+) TILs in gastric cancer tissue was analyzed by Pearson correlation analysis;telephone follow-up was conduct till to 36 months after operation,taking death or loss to follow-up as outcome event,Kaplan-Meier survivorship curve was drawn to conduct survival analysis;univariate and multivariate Cox regression analysis was used to analyze the influencing factors of prognosis of gastric cancer patients.Results The average relative expression quantity of PD-L1 mRNA was 3.1 in gastric cancer tissue,the average number of CD_(8)^(+) TILs was 36 in cancer nests,thus the 125 patients were divided into low-level group(with relative expression quantity of PD-L1 mRNA less than 3.1,n=73),high-level group(with relative expression quantity of PD-L1 mRNA equal or over 3.1,n=52),low-density group(with number of CD_(8)^(+) TILs less than 31,n=55)and high-density group(with number of CD_(8)^(+) TILs equal or over 31,n=70).There were significant differences in lymph node metastasis,vascular invasion and peritoneal metastasis between the the low-level group and high-level group(P<0.05),so as in depth of infiltration,incidence of lymphatic metastasis,vascular invasion and peritoneal metastasis between the the low-density group and high-density group(P<0.05).Pearson correlation analysis showed that the relative expression quantity of PD-L1 mRNA was negatively correlated with density of CD_(8)^(+) TILs in gastric cancer tissue(r=-0.412,P<0.001).We found 88 cases with good prognosis and 37 cases with poor prognosis,with the medium time of follow-up of 36 months;there was significant difference in Kaplan-Meier curve between low-level and high-level groups,low-density and high-density groups,respectively(P<0.05).Multivariate Cox regression analysis showed that high-level PD-L1 mRNA〔HR=3.021,95%CI(1.632,5.045)〕and low-density CD_(8)^(+) TILs〔HR=2.158,95%CI(1.854,4.632)〕were independent risk factors of poor prognosis of patients with gastric cancer(P<0.05).Conclusion High level of PD-L1 mRNA and low density of CD_(8)^(+) TILs are independent risk factors of poor prognosis in gastric cancer patients,which are expected to be biomarkers for poor prognosis in gastric cancer patients.