晚期肺腺癌瘤内趋化因子CCR1、CXCR6和CXCL9对免疫治疗的预测及预后作用分析

钟思敏; 张东东; 李扬秋; 吴一龙; 刘思阳; 金真伊

doi:10.12019/j.issn.1671-5144.202402013

晚期肺腺癌瘤内趋化因子CCR1、CXCR6和CXCL9对免疫治疗的预测及预后作用分析

Prediction and Prognosis Analysis for Immunotherapy of Intra-tumoral Chemokines CCR1, CXCR6, and CXCL9 in Advanced Lung Adenocarcinoma

摘要

摘要:
目的构建能够预测晚期肺腺癌（lung adenocarcinoma，LUAD）患者免疫检查点阻断（immune checkpoint blockade， ICB）治疗疗效与预后的趋化因子模型。
方法从既往研究数据中回顾性收集确诊为晚期LUAD且经过ICB治疗的42例患者（训练队列），取得其ICB治疗前肿瘤组织转录组测序数据，通过生物信息学方法，筛选出显著影响ICB治疗疗效与患者生存预后的趋化因子，通过无进展生存期（progression-free disease，PFS）评价疗效，通过总生存期（overall survival，OS）评价患者的预后。从高通量基因表达数据库（Gene Expression Omnibus，GEO）中的数据集（GSE 135222）下载25例非小细胞肺癌（non-small cell lung cancer，NSCLC）转录组测序数据和相关的生存数据，将其作为验证队列。
结果通过单因素Cox回归分析，筛选出9个与晚期LUAD患者良好OS显著相关的趋化因子，其中CCR1、CXCR6和CXCL9高表达的患者明显具有更长的OS。基于这3个趋化因子的表达量构建风险模型，生存分析结果表明风险分数与患者的PFS和OS呈负相关，即低风险（risk score ≤ −1.33）的晚期LUAD患者在ICB治疗中明显获益更多。低风险组中位PFS为19.7个月对比高风险组（risk score > −1.33）2.9个月95%可信区间（confidence interval，CI）为0.12~0.51，P < 0.001。中位OS低风险组未达到对比高风险组6.0个月（95%CI 0.08~0.38，P < 0.001）。GEO数据集验证了该结果，中位PFS低风险（risk score ≤ −1.85）对比高风险（risk score > −1.85）为2.7个月对比1.2个月（95%CI 0.12~0.93，P = 0.009）。
结论 CCR1、CXCR6和CXCL9高表达表明晚期LUAD患者疾病进展的风险较低，与患者良好的PFS和OS相关，可能为晚期LUAD患者的ICB辅助治疗提供新的方向。

Abstract:
Objective Constructing a chemokine model to predict immune checkpoint blockade (ICB) efficacy and prognosis in advanced lung adenocarcinoma (LUAD).
Methods A total of 42 advanced LUAD patients (training cohort) who underwent ICB were retrospectively collected from the data of the previous study. We obtained transcriptome sequencing data from tumor tissues before ICB treatment. Screening for chemokines that significantly affect the efficacy of ICB treatment and the survival prognosis of patients with advanced LUAD by bioinformatics methods, and the efficacy was evaluated by progression-free disease (PFS), and the prognosis was evaluated by overall survival (OS). Transcriptome sequencing and survival-related data of 25 cases of non-small cell lung cancer (NSCLC) were downloaded from the Gene Expression Omnibus (GEO) database dataset (GSE 135222) and identified as a validation cohort.
Results Through univariate Cox regression analysis, nine chemokines significantly associated with favorable OS in advanced LUAD patients were screened, among which patients with high expression of CCR1, CXCR6, and CXCL9 had significantly longer OS. A risk model based on the expression of these three chemokines could be constructed. Survival analysis results show that risk score was negatively correlated with patients’ PFS and OS, which means advanced LUAD patients with low risk (risk score ≤ −1.33) could benefit more from ICB treatment. The median PFS in the low-risk group was 19.7 months, whereas in the high-risk group (risk score > −1.33) was 2.9 months 95% confidence interval (CI) 0.12~0.51, P < 0.001, and the median OS in the high-risk group was 6.0 months, while it was not reached in the low-risk group (95%CI 0.08~0.38, P < 0.001). The results from the GEO dataset confirmed the association between the risk score and PFS. Patients were classified as low-risk based on the risk score (risk score ≤ −1.85) were associated with a longer median PFS of 2.7 months, whereas the high-risk group (risk score > −1.85) had a shorter median PFS of 1.2 months (95%CI 0.12~0.93, P = 0.009).
Conclusions The high expression of CCR1, CXCR6, and CXCL9 indicates that patients with advanced LUAD have a low risk of disease progression, which is associated with favorable PFS and OS, and may provide a novel perspective for the adjuvant setting of ICB therapy for advanced LUAD patients.

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