PD-1抑制剂治疗晚期肺癌的疗效及对患者外周血T淋巴细胞亚群和细胞因子水平的影响

Treatment efficacy of PD-1 inhibitor and its effect on the level of T lymphocyte subsets and cytokine in peripheral blood of patients with advanced lung cancer

目的:探讨PD-1抑制剂治疗晚期肺癌患者的疗效及其对患者外周血T淋巴细胞亚群及细胞因子水平的影响。方法:选择2018年8月至2020年12月于海口医院就诊的肺癌患者50例,选取同期体检健康者50例作为对照,免疫组化法检测肺癌组织中PD-1的表达。肺癌患者均接受纳武利尤单抗(nivolumab)或帕博利珠单抗(pembrolizumab)治疗,于治疗前1天、治疗1周期结束、治疗4周期结束时进行静脉血采集,治疗4周期后进行CT或MRI检查评价肿瘤大小,将评价为完全缓解(complete response,CR)、部分缓解(partial response,PR)和疾病稳定(stable disease,SD)的患者归为免疫应答组,评价为疾病进展(progressive disease,PD)的患者归为免疫无反应组。评估PD-1抑制剂治疗对患者外周血中T淋巴细胞亚群(CD3^(+)T细胞、CD4^(+)T细胞、CD8^(+)T细胞、CD4^(+)/CD8^(+)T细胞、Treg细胞及Th1/Th2细胞)、NK细胞和细胞因子(IFN-γ、IL-2、IL-4和IL-5)水平的影响。结果:与对照组相比,肺癌患者外周血中CD3^(+)T细胞、CD4^(+)T细胞、CD4^(+)/CD8^(+)T细胞、Th1/Th2细胞、IFN-γ和IL-2水平明显下降,而CD8^(+)T细胞、Treg细胞、NK细胞、IL-4和IL-5水平明显升高(均P<0.05);与治疗前相比,治疗1周期和4周期后CD3^(+)T细胞、CD4^(+)T细胞和CD4^(+)/CD8^(+)T细胞水平明显升高,而CD8^(+)T细胞、Treg细胞和NK细胞明显下降(均P<0.05);治疗4周期后,40例入免疫应答组,10例入免疫无反应组,治疗有效率为80%。与治疗无反应组比较,免疫应答组血清CD3^(+)T细胞、CD4^(+)T细胞、CD4^(+)/CD8^(+)T细胞水平和Th1/Th2比值明显升高,而CD8^(+)T细胞、Treg细胞和NK细胞水平明显下降(均P<0.05);免疫应答组患者经4个周期治疗后,与PD-L1低表达(<50%)患者(8例)比较,PD-L1高表达(≥50%)患者(32例)血清CD3^(+)T细胞、CD4^(+)T细胞和CD4^(+)/CD8^(+)T细胞水平均明显升高(均P<0.05),而CD8^(+)T细胞、Treg细胞和NK细胞均明显下降(均P<0.05)。结论:纳武利尤单抗或帕博利珠单抗治疗能够影响晚期肺癌患者T淋巴细胞亚群等免疫细胞分布,改善患者免疫状态。

Objective:To explore the efficacy of PD-1 inhibitors in the treatment of patients with advanced lung cancer and its influence on the T lymphocyte subsets and cytokine levels in the peripheral blood of patients.Methods:A total of 50 patients with lung cancer admitted to Haikou Hospital from August 2018 to December 2020 were selected,and 50 healthy subjects were selected as control.The expression of PD-1 expression in lung cancer tissues was detected by immunohistochemistry.Lung cancer patients were treated with nivolumab or pembrolizumab,and venous blood was collected at one day before treatment,the end of treatment cycle 1,and the end of treatment cycle 4.After 4 cycles of treatment,CT or MRI was performed to evaluate the tumor size.Patients evaluated with complete response(CR),partial response(PR),and stable disease(SD)were classified as an immune responsive group,and patients evaluated with progressive disease(PD)were classified as an immune non-responsive group.The effect of PD-1 inhibitor treatment on T lymphocyte subsets(CD3^(+)T,CD4^(+)T,CD8^(+)T,CD4^(+)/CD8^(+)T,Treg,and Th1/Th2 cells),NK cells,cytokines(IFN-γ,IL-2,IL-4,and IL-5)in peripheral blood of patients were evaluated.Results:Compared with healthy controls,the levels of CD3^(+)T,CD4^(+)T,CD4^(+)/CD8^(+)T,Th1/Th2 cells,IFN-γ,and IL-2 in peripheral blood of lung cancer patients were significantly decreased,while the levels of CD8^(+)T cells,Treg cells,NK cells,IL-4,and IL-5 were significantly increased(all P<0.05).Compared with pre-treatment,the levels of CD3^(+)T,CD4^(+)T,CD4^(+)/CD8^(+)T cells were significantly increased,while the levels of CD8^(+)T cells,Treg cells,and NK cells were significantly decreased after 1 and 4 cycles of treatment(all P<0.05).After 4 cycles of treatment,there were 40 cases in the immune responsive group and 10 cases in the non-immune responsive group,with an effective rate of 80%.Compared with the immune non[1]responsive group,the levels of CD3^(+)T,CD4^(+)T,CD4^(+)/CD8^(+)T,and Th1/Th2 cells were significantly increased in the immune response group,while the levels of CD8^(+)T cells,Treg cells,and NK cells were significantly decreased(all P<0.05);In the immune responsive group,there were 32 patients with high PD-L1 expression(≥50%)and 8 patients with low PD-L1 expression(<50%).Compared with patients with low PD-L1 expression,the levels of CD3^(+)T,CD4^(+)T,CD4^(+)/CD8^(+)T cells were significantly increased in patients with high PD-L1 expression,while the levels of CD8^(+)T cells,Treg cells,and NK cells were significantly decreased(all P<0.05).Conclusion:Nivolumab or pembrolizumab treatment can affect the distribution of immune cells such as T lymphocyte subsets in patients with advanced lung cancer and improve the immune status of patients.