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(P<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(P<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),P=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),P=0.018],ROC曲线表明其预测性能较好[AUCPFS=0.702,95%CI(0.562,0.842),P=0.027;AUCOS=0.684,95%CI(0.550,0.818),P=0.014]。虽然IL-11和IL-36A不能很好地预测NSCLC患者的PFS和OS(P>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(P=0.003)和3.0个月(P<0.001),ROC曲线表明其预测效能得到提升[AUCPFS=0.748,95%CI(0.615,0.880),P=0.007;AUCOS=0.703,95%CI(0.573,0.833),P=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。
【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(P<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),P=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),P=0.018].ROC curve showed that the prediction performance was favorable[AUCPFS=0.702,95%CI(0.562,0.842),P=0.027;AUCOS=0.684,95%CI(0.550,0.818),P=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(P=0.003)and 3.0 months(P<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[AUCPFS=0.748,95%CI(0.615,0.880),P=0.007;AUCOS=0.703,95%CI(0.573,0.833),P=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.
作者
钟思敏
张东东
郭舒月
张逸铠
刘思阳
金真伊
ZHONG Simin;ZHANG Dongdong;GUO Shuyue;ZHANG Yikai;LIU Siyang;JIN Zhenyi(College of Life Science and Technology,Jinan University,Guangzhou 510632,China;Department of Thoracic Surgery,The First Affiliated Hospital,Jinan University,Guangzhou 510630,China;Department of Pathology,School of Medicine,Jinan University,Guangzhou 510632,China;Guangdong Provincial Key Laboratory of Spine and Spinal Cord Reconstruction,The Fifth Affiliated Hospital,Heyuan Shenhe People's Hospital,Jinan University,Heyuan 517000,China;Key Laboratory for Regenerative Medicine of Ministry of Education,Institute of Hematology,School of Medicine,Jinan University,Guangzhou 510632,China;Guangdong Provincial People's Hospital Guangdong Academy of Medical Sciences,Guangdong Provincial Key Lab of Translational Medicine in Lung Cancer,Guangzhou 510080,China;Guangdong Lung Cancer Institute,Guangdong Provincial People's Hospital,Southern Medical University,Guangzhou 510080,China;Department of Hematology,The First Affiliated Hospital,Jinan University,Guangzhou 510630,China)
出处
《中山大学学报（医学科学版）》
CAS
CSCD
北大核心
2024年第4期557-566,共10页
Journal of Sun Yat-Sen University:Medical Sciences
基金
国家自然科学基金(82202997)
广东省自然科学基金项目(2023A1515030271)
中国博士后科学基金(2021M701422)
广东省临床试验协会/中国胸部肿瘤研究协作组和广东省肺癌转化医学重点实验室开放课题(2017B030314120)。
