外周调节性细胞在接受非小细胞肺癌放疗患者中的运用

易军; 陶黎明; 王帆; 胡贤春; 刘力

doi:10.3969/j.issn.1000-8179.2019.02.976

外周调节性细胞在接受非小细胞肺癌放疗患者中的运用

Clinical value of peripheral regulatory cells in patients with non-small cell lung cancer undergoing radiotherapy

摘要

摘要:
目的探讨外周调节性T细胞、NK细胞及T淋巴细胞亚群在接受放疗的非小细胞肺癌(non-small cell lung cancer, NSCLC)患者中的预测价值。
方法选择2016年1月至2017年12月九江市第三人民医院105例NSCLC患者及同期体格检查的45例健康受试者进行研究, 其中62例为初诊患者, 43例为复发患者。抽取患者空腹外周静脉血对其淋巴细胞亚群进行检查, 并采用单因素与多因素分析NSCLC无进展生存的影响因素。
结果与健康对照组相比, NSCLC患者CD4⁺CD25⁺Foxp3⁺调节性T细胞的比例显著升高(P < 0.05); NSCLC患者复发时CD4⁺CD25⁺Foxp3⁺调节性T细胞高表达与初诊患者相比得到进一步验证, CD19⁺B细胞、CD4⁺T细胞和CD4/CD8比值显著下降, NSCLC患者CD8⁺T细胞和CD8⁺CD28^-T细胞明显增加(P < 0.05), 而NK、NKT、γδT、CD3⁺、CD8⁺ CD28⁺T细胞在患者与对照组之间无显著性差异(P > 0.05)。40例复发患者中, 转移患者与复发患者相比, CD4⁺CD25⁺Foxp3⁺调节性T细胞增多; CD4⁺T细胞比例、CD4/CD8比值下降, 差异具有统计学意义(P < 0.05)。CD4⁺CD25⁺Foxp3⁺调节性T细胞比例高与无进展生存期相关(HR=2.55, 95%CI:1.07~6.11, P=0.019)。其他淋巴细胞亚群与无进展生存期之间无显著性关联。除淋巴细胞亚群外, 其中性粒细胞/淋巴细胞比率与无进展生存期呈负相关(HR=2.66, 95%CI:1.01~7.05, P=0.033), 淋巴细胞与无进展生存期呈正相关(HR=0.42, 95%CI:0.17~1.03, P=0.042)。根据临床病理特点, NSCLC患者的肿瘤分化程度、T分期、N分期与临床预后相关(P < 0.05)。多因素分析结果显示, 无进展生存的独立性影响因素为CD4⁺CD25⁺Foxp3⁺调节性T细胞及N分期(P < 0.05)。疾病进展患者调节性T细胞高表达比例显著高于疾病稳定、部分缓解及完全缓解的患者(P < 0.05)。通过受试者工作特征曲线(ROC)对外周调节性T细胞预测NSCLC无进展生存的诊断效能进行分析, AUC为0.915, 当最佳阈值取2.85时, 外周调节性T细胞预测NSCLC患者无进展生存的预测敏感性为87.7%, 特异性为71.4%。
结论 NSCLC放疗患者外周血CD4⁺CD25⁺Foxp3⁺调节性T细胞增多, 是NSCLC进展的独立性影响因素, 具有预测NSCLC患者预后的作用。

Abstract:
Objective To investigate the predictive value of peripheral regulatory T cells, NK cells, and T lymphocyte subsets in patients with non-small cell lung cancer (NSCLC) receiving radiotherapy.
Methods From January 2016 to December 2017, 105 patients with NSCLC and 45 healthy volunteers were enrolled in the study. Sixty-two patients were newly diagnosed, and 43 patients had relapsed. The lymphocyte subsets of patients with NSCLC were examined in fasting peripheral venous blood samples, and the influencing factors of progression-free survival were analyzed through univariate and multivariate analyses.
Results Compared with the healthy control group, the proportion of CD4⁺CD25⁺Foxp3⁺ regulatory T cells in NSCLC patients was significantly higher (P < 0.05); the high expression of CD4⁺CD25⁺Foxp3⁺ regulatory T cells in recurrent NSCLC patients was further confirmed compared with the newly diagnosed patients. CD19⁺ B cells, CD4⁺ cells and the ratio of CD4/CD8 was significantly decreased and CD8⁺T cells as well as CD8⁺CD28^-T cells were significantly increased in NSCLC patients (P < 0.05). There was no significant difference in NK, NKT, γδT, CD3⁺, and CD8⁺CD28⁺T cells between patients and controls (P > 0.05). In 40 patients with recurrence, the number of regulatory T cells increased compared with that in patients with relapse, and the proportion of CD4⁺T cells and ratio of CD4/CD8 decreased. The difference was statistically significant (P < 0.05). The high proportion of regulatory T cells was associated with progression-free survivalhazard ratio (HR)=2.55, 95% confidence interval (CI):1.07 to 6.11, P=0.019. There was no significant association between other lymphocyte subsets and progression-free survival. In addition to lymphocyte subsets, the neutrophil/lymphocyte ratio was negatively correlated with progression-free survival (HR= 2.66, 95%CI:1.01 to 7.05, P=0.033). There was a positive correlation between lymphocyte and progression-free survival (HR=0.42, 95% CI:0.17 to 1.03, P=0.042). According to clinicopathological features, the degree of tumor differentiation, T stage, and N stage in NSCLC patients were related to clinical prognosis (P < 0.05). Multivariate analysis showed that the independent factors affecting progressionfree survival were CD4⁺CD25⁺Foxp3⁺ regulatory T cells and N stage (P < 0.05). The proportion of regulatory T cells in patients with disease progression was significantly higher than that in patients with stable disease, partial remission, and complete remission (P < 0.05). The diagnostic efficacy of peripheral CD4⁺CD25⁺Foxp3⁺ regulatory T cells in predicting progression-free survival in patients with NSCLC was analyzed using a receiver-operating characteristic curve (ROC) with an area under the curve of 0.915. When the optimal threshold was 2.85, the predictive sensitivity of peripheral CD4⁺CD25⁺Foxp3⁺ regulatory T cells for progression-free survival in NSCLC patients was 87.7% and the specificity was 71.4%.
Conclusions CD4⁺CD25⁺Foxp3⁺ regulatory T cells in crease in the peripheral blood of patients with NSCLC receiving radiotherapy and play as an independent factor in the progression of NSCLC. CD4⁺CD25⁺Foxp3⁺ regulatory T cells can predict the prognosis of patients with NSCLC.

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