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中华肺部疾病杂志(电子版)

中华肺部疾病杂志(电子版) ›› 2025, Vol. 18 ›› Issue (04) : 558 -563. doi: 10.3877/cma.j.issn.1674-6902.2025.04.011

论著

血浆细胞因子谱预测非小细胞肺癌患者临床获益和免疫相关不良事件的意义
蒋延龄, 任瑾卓, 陈俊杰, 田秀丽, 莘翼翔, 张华†()   
  1. 075000　张家口，张家口市第一医院·张家口学院直属附属医院呼吸内科
  • 收稿日期:2025-04-23 出版日期:2025-08-25
  • 通信作者: 张华
  • 基金资助:
    张家口市重点研发计划项目(2322126D); 河北省卫生健康委科研基金项目(20211820)

Significance of plasma cytokine profile in predicting clinical benefits and immune related adverse events in patients with non-small cell lung cancer

Yanling Jiang, Jinzhuo Ren, Junjie Chen, Xiuli Tian, Yixiang Shen, Hua Zhang†()   

  1. Department of Respiratory Medicine, Zhangjiakou First Hospital(Zhangjiakou University Affiliated Hospital), Zhangjiakou 075000, China
  • Received:2025-04-23 Published:2025-08-25
  • Corresponding author: Hua Zhang
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引用本文：

蒋延龄, 任瑾卓, 陈俊杰, 田秀丽, 莘翼翔, 张华. 血浆细胞因子谱预测非小细胞肺癌患者临床获益和免疫相关不良事件的意义[J/OL]. 中华肺部疾病杂志(电子版), 2025, 18(04): 558-563.

Yanling Jiang, Jinzhuo Ren, Junjie Chen, Xiuli Tian, Yixiang Shen, Hua Zhang. Significance of plasma cytokine profile in predicting clinical benefits and immune related adverse events in patients with non-small cell lung cancer[J/OL]. Chinese Journal of Lung Diseases(Electronic Edition), 2025, 18(04): 558-563.

目的

分析血浆细胞因子谱及免疫检查点抑制剂(immune checkpoint inhibitors, ICIs)对非小细胞肺癌(non-small cell lung cancer, NSCLC)患者临床益处和免疫相关不良事件(irAE)的相关性。

方法

选择2020年1月至2024年10月我院收治的56例不可切除Ⅲ~Ⅳ期晚期NSCLC患者为对象，33例接受ICIs单药治疗，23例经ICIs联合治疗，持续临床获益(durable clinical benefit, DCB)33例为观察组，非持续临床获益(non-durable clinical benefit, NDB) 23例为对照组。分析两组临床特征、血浆炎性细胞因子和全血细胞计数，筛选与临床益处和irAE相关生物标志物。

结果

56例中位无进展生存期9.0个月(95%CI：4.41~13.6)。免疫部分缓解(immune partial response, iPR) 21例(37.50%)、免疫稳定疾病(immune stable disease, iSD) 14例(25.0%)、未确认进展(immune unconfirmed progressive disease, iUPD)13例(23.21%)，免疫明确进展(immune confirmed progressive disease, iCPD) 8例(14.29%)。对照组治疗前IL-6(P＝0.024)、IL-10(P＝0.035)和NLR(P＝0.005)高于观察组。对照组治疗后IL-6变化值2.14 pg/ml、IL-10变化值1.88 pg/ml高于观察组IL-6变化值－1.95 pg/ml(Z＝－3.123，P＝0.002)、IL-10变化值－0.27 pg/ml(Z＝－2.773，P＝0.006)。ROC曲线分析显示，IL-6和IL-10变化值鉴别DCB和NDB曲线下面积分别为0.747(95%CI：0.613~0.854)和0.701(95%CI：0.583~0.831)。Cox回归显示，治疗前NLR(HR＝1.103，95%CI：1.001~1.153，P＝0.041)及ICIs治疗过程IL-6(HR＝2.027，95%CI：1.001~4.258，P＝0.019)和IL-10升高(HR＝2.053，95%CI：1.018~4.089，P＝0.002)是影响无进展生存时间的危险因素。56例中33例(58.93%)至少发生一种irAE。治疗前IL-6(HR＝4.458，95%CI：1.329~14.953，P＝0.015)及ICIs治疗过程血浆IL-10升高(HR＝5.712，95%CI：1.088~29.993，P＝0.039)是影响irAE的预测因素，预测irAE的ROC曲线下面积分别为0.754和0.706。免疫相关肺炎患者血浆IL-6高于其他患者，ICIs治疗过程中血浆IL-10呈降低趋势(P<0.05)。

结论

血浆细胞因子谱是轻度无创、易于获得和可重复指标，IL-6和IL-10可作为晚期NSCLC患者ICIs治疗生物标志物。

关键词: 非小细胞肺癌, 血浆细胞因子谱, 免疫检查点抑制剂, 肿瘤反应, 免疫相关不良事件
Objective

To analyze the correlation between plasma cytokine profiles, immune checkpoint inhibitors (ICIs), clinical benefits, and immune-related adverse events (irAEs) in patients with non-small cell lung cancer (NSCLC).

Methods

A total of 56 patients with unresectable stage Ⅲ~Ⅳ advanced NSCLC treated at our hospital from January 2020 to October 2024 were enrolled. Among them, 33 received ICIs monotherapy and 23 received combination ICIs therapy. 33 patients with durable clinical benefit (DCB) were assigned to the observation group, while 23 cases with non-durable clinical benefit (NDB) served as the control group. Clinical characteristics, plasma inflammatory cytokines, and complete blood counts were analyzed to identify biomarkers associated with clinical benefits and irAEs.

Results

The median progression-free survival (PFS) for all 56 patients was 9.0 months (95%CI: 4.41~13.6). Immune partial response (iPR) was observed in 21 patients (37.50%), immune stable disease (iSD) in 14 (25.0%), immune unconfirmed progressive disease (iUPD) in 13 (23.21%), and immune confirmed progressive disease (iCPD) in 8 (14.29%). Pretreatment levels of IL-6 (P=0.024), IL-10 (P=0.035), and neutrophil-to-lymphocyte ratio (NLR, P=0.005) were higher in the control group compared to the observation group. Post-treatment changes in IL-6+ 2.14 pg/ml and IL-10 + 1.88 pg/ml in the control group exceeded those in the observation group (IL-6: 1.95 pg/ml, Z=3.123, P=0.002; IL-10: 0.27 pg/ml, Z=2.773, P=0.006). ROC curve analysis revealed that changes in IL-6 and IL-10 differentiated DCB from NDB with areas under the curve (AUC) of 0.747 (95%CI: 0.613~0.854) and 0.701 (95%CI: 0.583~0.831), respectively. Cox regression indicated that pretreatment NLR (HR=1.103, 95%CI=1.001~1.153, P=0.041) and elevated IL-6 (HR=2.027, 95%CI: 1.001~4.258, P=0.019) and IL-10 (HR=2.053, 95%CI: 1.018~4.089, P=0.002) during ICIs treatment were risk factors for reduced PFS. Among the 56 patients, 33 (58.93%) experienced at least one irAE. Pretreatment IL-6 (HR=4.458, 95%CI: 1.329~14.953, P=0.015) and increased IL-10 during ICIs therapy (HR=5.712, 95%CI: 1.088~29.993, P=0.039) were predictive of irAEs, with AUCs of 0.754 and 0.706, respectively. Patients with immune-related pneumonia exhibited higher plasma IL-6 levels, while IL-10 decreased during ICIs treatment (P<0.05).

Conclusion

Plasma cytokine profiling is a minimally invasive, accessible, and reproducible approach. IL-6 and IL-10 may serve as biomarkers for predicting clinical outcomes and irAEs in advanced NSCLC patients undergoing ICIs therapy.

Key words: Non-small cell lung cancer, Plasma cytokine profile, Immune checkpoint inhibitors, Tumor response, Immune-related adverse events
表1 两组NSCLC患者ICIs治疗前血浆细胞因子谱比较[M(M25，M75)]
检测指标 观察组(n＝33) 对照组(n＝23) Z值 P值
IL-1β(pg/ml) 0.12(0.06，0.36) 0.13(0.07，0.27) －1.117 0.264
IL-2(pg/ml) 0.31(0.21，0.63) 0.34(0.25，0.54) －1.166 0.244
IL-4(pg/ml) 0.02(0.02，0.03) 0.03(0.02，0.06) －0.225 0.822
IL-6(pg/ml) 7.83(3.38，12.81) 9.21(5.40，26.98) －2.257 0.024
IL-8(pg/ml) 6.01(4.46，12.04) 7.05(6.53，13.56) －1.557 0.119
IL-10(pg/ml) 5.53(0.91，12.10) 11.61(1.83，17.24) －2.122 0.035
IL-12p70(pg/ml) 0.26(0.16，0.42) 0.18(0.16，0.43) －0.816 0.414
IL-13(pg/ml) 1.44(1.07，2.01) 1.53(1.41，1.86) －0.064 0.949
IFN-γ(pg/ml) 11.56(6.98，21.80) 12.28(9.33，19.75) －0.529 0.597
TNF-α(pg/ml) 5.81(4.57，7.68) 6.14(4.66，7.23) －0.724 0.469
白细胞计数(×109个/ml) 7.20(6.12，9.29) 6.99(6.44，7.65) －1.499 0.134
中性粒细胞计数(×109个/ml) 4.49(3.99，5.92) 4.52(3.65，6.21) －1.807 0.071
淋巴细胞计数(×109个/ml) 1.24(1.09，1.86) 1.24(0.81，1.81) －0.317 0.807
NLR 3.53(2.76，5.21) 5.37(3.98，14.07) －2.806 0.005
C反应蛋白(pg/ml) 0.15(0.01，1.12) 0.21(0.01，1.24) －0.302 0.583
图1 NSCLC患者预后Kaplan-Meier生存曲线
表2 晚期NSCLC患者疾病进展影响因素Cox回归分析
自变量 单变量分析 多变量分析
HR(95%CI) P值 HR(95%CI) P值
DCB(DCB vs. NDB) 0.054(0.020~0.147) 0.000 0.071(0.097~0.377) 0.021
PD-L1检测(阳性率≥25% vs.阳性率<25%) 0.307(0.141~0.668) 0.003 0.374(0.081~1.038) 0.083
NLR 1.073(1.036~1.112) 0.000 1.103(1.001~1.153) 0.041
IL-6 2.328(1.236~4.382) 0.001 2.027(1.001~4.258) 0.019
IL-10 2.326(1.166~4.637) 0.000 2.053(1.018~4.089) 0.002
图2 图A为晚期NSCLC患者IL-6和IL-10预测irAE ROC曲线；图B为免疫相关肺炎患者血浆IL-6及ICIs治疗过程中血浆IL-10水平变化
表3 irAE危险因素的单变量和多变量Cox回归分析
自变量 单变量分析 多变量分析
HR(95%CI) P值 HR(95%CI) P值
现在/既往吸烟史(是vs.否) 2.136(1.135~4.018) 0.019 1.807(0.943~3.463) 0.074
ECOG PS评分(1分vs. 0分) 0.295(0.019~0.998) 0.029 0.441(0.095~2.055) 0.297
治疗前        
IL-6 5.537(1.689~18.152) 0.005 4.458(1.329~14.953) 0.015
治疗后较治疗前变化值 2.739(0.958~7.832) 0.060 2.279(0.739~7.027) 0.152
IL-6 4.375(1.027~18.629) 0.046 2.359(0.464~12.006) 0.301
IL-10 7.857(1.651~37.403) 0.010 5.712(1.088~29.993) 0.039
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