Prediction and Prognosis for Immunotherapy of Intra-tumoral Interleukins Expression Patterns in Non-small Cell Lung Cancer

ZHONG Simin; ZHANG Dongdong; GUO Shuyue; ZHANG Yikai; LIU Siyang; JIN Zhenyi

doi:10.13471/j.cnki.j.sun.yat-sen.univ（med.sci）.2024.0408

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Prediction and Prognosis for Immunotherapy of Intra-tumoral Interleukins Expression Patterns in Non-small Cell Lung Cancer

Preclinic Research | 更新时间：2024-07-30

- Prediction and Prognosis for Immunotherapy of Intra-tumoral Interleukins Expression Patterns in Non-small Cell Lung Cancer
- Journal of Sun Yat-sen University(Medical Sciences) Vol. 45, Issue 4, Pages: 557-566(2024)
- 作者机构：
  
  1.暨南大学生命科学技术学院，广东广州 510632
  2.暨南大学第一附属医院胸外科，广东广州 510630
  3.暨南大学基础医学与公共卫生学院病理学系，广东广州 510632
  4.暨南大学附属第五医院//河源深河人民医院广东省脊柱与脊髓重建重点实验室，广东河源 517000
  5.暨南大学基础医学与公共卫生学院血液学研究所//再生医学教育部重点实验室，广东广州 510632
  6.广东省人民医院//广东省医学科学院广东省肺癌转化医学重点实验室，广东广州 510080
  7.广东省人民医院//南方医科大学广东省肺癌研究所，广东广州 510080
  8.暨南大学第一附属医院血液科，广东广州 510630
- 作者简介：
  
  LIU Siyang， E-mail： siyangliu2020@outlook.com
  JIN Zhenyi， E-mail： jinzhenyi11@jnu.edu.cn
- 基金信息：
- DOI：10.13471/j.cnki.j.sun.yat-sen.univ（med.sci）.2024.0408
  CLC： R734.2
- Published：20 July 2024，
  
  Received：08 May 2024，
  
  Accepted：19 June 2024
- 稿件说明：
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钟思敏,张东东,郭舒月等.非小细胞肺癌肿瘤白细胞介素的表达模式对免疫治疗疗效和预后的作用[J].中山大学学报（医学科学版）,2024,45(04):557-566.

ZHONG Simin,ZHANG Dongdong,GUO Shuyue,et al.Prediction and Prognosis for Immunotherapy of Intra-tumoral Interleukins Expression Patterns in Non-small Cell Lung Cancer[J].Journal of Sun Yat-sen University(Medical Sciences),2024,45(04):557-566.
钟思敏,张东东,郭舒月等.非小细胞肺癌肿瘤白细胞介素的表达模式对免疫治疗疗效和预后的作用[J].中山大学学报（医学科学版）,2024,45(04):557-566. DOI： 10.13471/j.cnki.j.sun.yat-sen.univ（med.sci）.2024.0408.

ZHONG Simin,ZHANG Dongdong,GUO Shuyue,et al.Prediction and Prognosis for Immunotherapy of Intra-tumoral Interleukins Expression Patterns in Non-small Cell Lung Cancer[J].Journal of Sun Yat-sen University(Medical Sciences),2024,45(04):557-566. DOI： 10.13471/j.cnki.j.sun.yat-sen.univ（med.sci）.2024.0408.

摘要

目的

为了明确对免疫检查点阻断（ICB）治疗应答反应较差的非小细胞肺癌（NSCLC）患者与肿瘤组织白细胞介素（ILs）表达水平之间的潜在关联，探讨其在NSCLC患者肿瘤中的表达差异及其对患者ICB疗效和预后的影响。

方法

从既往研究数据中回顾性收集确诊为NSCLC且经过ICB治疗的61例患者，取得其ICB治疗前的肿瘤组织转录组测序及生存相关的数据，通过生物信息学方法，筛选出显著影响患者ICB治疗疗效与预后的ILs，以无进展生存期（PFS）评价疗效和总生存期（OS）评价患者的预后，使用Kaplan-Meier生存曲线和ROC曲线分析ILs对NSCLC患者ICB疗效和预后的预测作用及效能。

结果

通过单因素Cox回归分析，筛选出9个与NSCLC患者OS相关的ILs（

0.1），经过多因素Cox回归分析进一步筛选得到与NSCLC患者不良预后显著相关的ILs，结果提示

IL-11、IL-17D

和

IL-36A

高表达与NSCLC患者ICB治疗的不良预后相关（

0.05）。Kaplan-Meier生存曲线结果表明

IL-17D

高表达与NSCLC患者的PFS和OS显著负相关，高表达患者的中位PFS为3.1个月对比低表达患者6.5个月［95%CI为（1.178，3.655），

= 0.009］，中位OS高表达组对比低表达组为9.8个月对比21.8个月［95%CI（1.116，4.392），

= 0.018］，ROC曲线表明其预测性能较好［AUC

PFS

= 0.702，95%CI（0.562，0.842），

= 0.027；AUC

= 0.684，95%CI（0.550，0.818），

= 0.014］。虽然

IL-11

和

IL-36A

不能很好地预测NSCLC患者的PFS和OS（

0.05），但当两者与

IL-17D

的表达模式联合时，发现上述3种ILs均为高表达的NSCLC患者，中位PFS与OS分别缩短至2.2个月（

= 0.003）和3.0个月（

0.001），ROC曲线表明其预测效能得到提升［AUC

PFS

= 0.748，95%CI（0.615，0.880），

= 0.007；AUC

= 0.703，95%CI（0.573，0.833），

= 0.007］。

结论

IL-11

、

IL-17D

和

IL-36A

高表达提示NSCLC患者疾病进展的风险较高，与患者不良的PFS和OS相关，可能为NSCLC的ICB辅助治疗提供新的策略。

Abstract

Objective

To identify the relationship between tumor tissue interleukins （ILs） and non-small cell lung cancer （NSCLC） patients with poor response to immune checkpoint blockade （ICB） therapy， and to investigate the differential expression of ILs in tumor of NSCLC patients as well as its effect on ICB response and prognosis.

Methods

A total of 61 patients diagnosed with NSCLC and treated with ICB were retrospectively collected from the data of a previous study. We obtained transcriptome sequencing data from tumor tissues and survival data of the patients before ICB treatment. Using bioinformatics methods， we screened for ILs that significantly affected the efficacy and prognosis of ICB treatment. We evaluated the efficacy of ICB treatment using progressive-free survival （PFS） and assessed the prognosis using overall survival （OS）. The Kaplan-Meier survival curve and ROC curve were used to analyze the predictive effect and efficacy of ILs on the efficacy and prognosis of ICB in NSCLC patients.

Results

The results of the univariate Cox regression analysis in our study showed that nine ILs were found to be associated with OS of NSCLC patients treated with ICB at a significance level of P

0.1. Further multivariate analysis revealed that high expression of

IL-11

，

IL-17D

， and

IL-36A

was significantly associated with poor prognosis in these patients （

0.05）. The results from the Kaplan-Meier survival curve analysis revealed a significant negative correlation between the high expression of

IL-17D

and both PFS and OS in NSCLC patients. Specifically， patients with

IL-17D

high expression had a median PFS of 3.1 months compared with 6.5 months in low expression patients ［95% confidence interval （CI）（1.178， 3.655），

= 0.009］. Similarly， the median OS was 9.8 months in the high expression group versus 21.8 months in the low expression group ［95%CI （1.116， 4.392），

= 0.018］. ROC curve showed that the prediction performance was favorable ［AUC

PFS

= 0.702，95%CI （0.562， 0.842），

= 0.027； AUC

= 0.684， 95%CI （0.550， 0.818），

= 0.014］. Although

IL-11

and

IL-36A

alone were not significant predictors of PFS and OS in NSCLC patients， the median PFS and OS were notably shortened to 2.2 months （

= 0.003） and 3.0 months （

0.001）， respectively， when high expression of

IL-11

and

IL-36A

was combined with high expression of

IL-17D

. The ROC curve analysis demonstrated an improvement in prediction efficiency for both PFS and OS in NSCLC patients ［AUC

PFS

= 0.748， 95%CI （0.615， 0.880），

= 0.007； AUC

= 0.703， 95%CI （0.573， 0.833），

= 0.007］.

Conclusion

The results suggest that high expression of

IL-11

，

IL-17D

， and

IL-36A

is associated with a higher risk of disease progression which correlates to poor PFS and OS in NSCLC patients.

关键词

IL-11IL-17DIL-36A非小细胞肺癌免疫检查点阻断治疗

Keywords

IL-11IL-17DIL-36Anon-small cell lung cancerimmune checkpoint blockade therapy

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Related Author

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Related Institution

Key Laboratory for Regenerative Medicine of Ministry of Education， Institute of Hematology， School of Medicine， Jinan University

School of Basic Medical Sciences， Hebei North University

Department of Thoracic surgery， The First Affiliated Hospital of USTC

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