宫颈癌淋巴结转移患者PD-L1与TILs表达水平及其与预后的关系

Expression levels of PD-L1 and TILs and their relationship with prognosis in cervical cancer patients with lymph node metastasis

目的探讨宫颈癌淋巴结转移患者程序性死亡配体-1(PD-L1)、肿瘤浸润淋巴细胞亚群(TILs)表达水平及其与患者预后的关系。方法选取2007年1月至2013年9月在梅州市人民医院诊治并接受宫颈癌根治性切除术后发生淋巴结转移的101例患者作为研究对象。采用免疫组织化学法检测PD-L1、CD4^(+)TILs、CD8^(+)TILs、叉头翼螺旋转录因子3(Foxp3)^(+)TILs表达水平。比较不同PD-L1表达水平患者临床病理特征差异;采用Spearman相关对PD-L1表达水平与TILs密度的相关性进行分析;采用Kaplan-Meier生存分析法分析PD-L1表达水平、TILs密度及密度比值与累计生存率的关系;采用Cox比例风险模型分析患者预后的独立影响因素。结果PD-L1表达于肿瘤细胞的细胞质和(或)细胞膜,阳性表达率为34.65%(35/101);CD4^(+)TILs计数为94(45,190);CD8^(+)TILs计数为63(31,117);FoxP3^(+)TILs计数为6.0(2.5,13.5);FoxP3^(+)TILs/CD8^(+)TILs比值为0.109(0.036,0.193)。PD-L1阳性表达组与PD-L1阴性表达组CD4^(+)TILs、CD8^(+)TILs、FoxP3^(+)TILs密度比较,差异均有统计学意义(P<0.05)。PD-L1表达情况与CD4^(+)TILs、CD8^(+)TILs、FoxP3^(+)TILs密度均呈正相关(r=0.305、0.222、0.222,P=0.002、0.026、0.026)。生存组与死亡组CD4^(+)TILs密度、CD8^(+)TILs密度和PD-L1表达情况比较,差异均有统计学意义(P<0.05)。手术年龄<50岁、PD-L1阳性表达、CD4^(+)TILs高密度、CD8^(+)TILs高密度、FoxP3^(+)TILs/CD8^(+)TILs低比值患者累计生存率均高于手术年龄≥50岁、PD-L1阴性表达、CD4^(+)TILs低密度、CD8^(+)TILs低密度、FoxP3^(+)TILs/CD8^(+)TILs高比值患者,差异均有统计学意义(P<0.05)。多因素Cox回归分析结果显示,PD-L1阳性表达、CD8^(+)TILs高密度是患者预后的独立保护因素(P<0.05)。结论PD-L1、CD4^(+)TILs、CD8^(+)TILs、FoxP3^(+)TILs/CD8^(+)TILs比值与宫颈癌淋巴结转移患者预后均有关,其中PD-L1阳性表达、CD8^(+)TILs高密度是宫颈癌淋巴结转移患者预后的独立保护因素。

Objective To investigate the expression of programmed death ligand-1(PD-L1)and tumor infiltrating lymphocyte subsets(TILs)in cervical cancer patients with lymph node metastasis and their relationship with prognosis.Methods A total of 101 patients with lymph node metastasis after radical resection of cervical cancer in Meizhou People′s Hospital from January 2007 to September 2013 were selected as the research objects.The expression levels of PD-L1,CD4^(+)TILs,CD8^(+)TILs and forkhead wing helix transcription factor 3(Foxp3)^(+)TILs were detected by immunohistochemistry.The differences in clinicopathological characteristics of patients with different PD-L1 expression were compared.Spearman correlation was used to analyze the correlation between PD-L1 expression level and TILs density.Kaplan-Meier survival analysis was used to analyze the relationship between PD-L1 expression level,TILs density,density ratio and cumulative survival rate.Cox proportional hazards model was used to analyze the independent prognostic factors of patients.Results PD-L1 was expressed in the cytoplasm and/or cell membrane of tumor cells,and the positive expression rate was 34.65%(35/101).CD4^(+)TILs count was 94(45,190).CD8^(+)TILs count was 63(31,117).FoxP3^(+)TILs was 6.0(2.5,13.5).The ratio of FoxP3^(+)TILs/CD8^(+)TILs was 0.109(0.036,0.193).There were significant differences in the density of CD4^(+)TILs,CD8^(+)TILs and FoxP3^(+)TILs between the PD-L1 positive expression group and the PD-L1 negative expression group(P<0.05).The expression of PD-L1 was positively correlated with the density of CD4^(+)TILs,CD8^(+)TILs and FoxP3^(+)TILs(r=0.305,0.222,0.222,P=0.002,0.026,0.026).There were significant differences in the density of CD4^(+)TILs,CD8^(+)TILs and PD-L1 expression between the survival group and the death group(P<0.05).Cumulative survival rate of patients with surgical age<50 years,PD-L1 positive expression,high density of CD4^(+)TILs,high density of CD8^(+)TILs,and low ratio of FoxP3^(+)TILs/CD8^(+)TILs are higher than that of patients with surgical age≥50 years,PD-L1 negative expression,CD4^(+)TILs low density,CD8^(+)TILs low density,high FoxP3^(+)TILs/CD8^(+)TILs ratio patients,the differences were statistically significant(P<0.05).Multivariate Cox regression analysis showed that PD-L1 positive expression and high density of CD8^(+)TILs were independent protective factors for the prognosis of patients(P<0.05).Conclusion PD-L1,CD4^(+)TILs,CD8^(+)TILs and FoxP3^(+)TILs/CD8^(+)TILs are ratio associated with the prognosis of cervical cancer patients with lymph node metastasis.Positive expression of PD-L1 and high density of CD8^(+)TILs are independent protective factors for the prognosis of cervical cancer patients with lymph node metastasis.