NOTCH1突变可预测免疫检查点阻断疗法在非小细胞肺癌中的卓越疗效

IF 6.2 Q1 IMMUNOLOGY
Qingyuan Huang, Hang Cao, Q. Yao, Xiaoyan Zhou, Hang Li, Q. Bai, Hong Hu
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引用次数: 0

摘要

背景NOTCH1在非小细胞肺癌(NSCLC)中经常发生突变,也是一个较差的治疗靶点。研究NOTCH1突变对抗肿瘤免疫和免疫检查点阻断(immune checkpoint blockade, ICB)应答的影响具有重要的临床意义。方法对963例非小细胞肺癌患者进行靶向测序观察性研究(FUSCC队列)。对癌症基因组图谱泛肺癌研究(TCGA队列)数据进行分析,并进行基因集富集分析(GSEA)。Samstein等人的队列包括350例晚期NSCLC患者,他们接受了MSK-IMPACT测定的基因组分析,并接受了至少一剂量的ICB治疗。结果NOTCH1突变在吸烟者和鳞状细胞癌(SCC)患者中更为常见(P值均<0.05)。对于未接受ICB治疗的患者(TCGA队列),notch1突变患者和-WT患者的总生存期(OS)相当(log-rank P = 0.72),而在Samstein等队列中,接受ICB治疗的患者,notch1突变患者的OS显著优于WT患者(log-rank P = 0.041)。多变量Cox分析显示,NOTCH1突变的预测价值达到了边际统计学意义(HR, 0.42;95% ci, 0.17-1.04;P = 0.059)。NOTCH1突变肿瘤的TMB中位数明显高于NOTCH1- wt肿瘤,GSEA显示NOTCH1突变在DNA损伤修复中表现出多种缺陷。notch1突变肿瘤表现为炎症性肿瘤微环境(TME),表现为PD-L1表达增加和肿瘤浸润CD8+ T细胞。结论NOTCH1突变定义了NSCLC的一个分子亚型,该亚型在吸烟者和SCC患者中更为常见,其特征是TMB升高,TME发炎,并且ICB治疗可提高NSCLC患者的生存率。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
NOTCH1 Mutations Predict Superior Outcomes of Immune Checkpoint Blockade in Non-Small Cell Lung Cancer
Background NOTCH1 is frequently mutated in non-small cell lung cancer (NSCLC), and also is a poor therapeutic target. It is of clinical importance to investigate the effects of NOTCH1 mutations on anti-tumor immunity and response to immune checkpoint blockade (ICB). Methods An observational study with targeted sequencing in 963 NSCLC patients at our center were performed (FUSCC cohort). Data of the Cancer Genome Atlas Pan-Lung Cancer study (TCGA cohort) were analyzed, and gene set enrichment analysis (GSEA) was performed. The Samstein et al cohort included 350 patients with advanced NSCLC undergoing genomic profiling with the MSK-IMPACT assay, and receiving at least one dose of ICB therapy. Results NOTCH1 mutations were more common in smokers and patients with squamous-cell carcinoma (SCC) (all P value <0.05). For patients who did not receive ICB therapy (TCGA cohort), the overall survival (OS) of NOTCH1-mutant and -WT patients were comparable (log-rank P = 0.72), while for patients who received ICB therapy in the Samstein et al cohort, NOTCH1-mutant patients had significantly superior OS than WT patients (log-rank P = 0.041). On multivariate Cox analysis, the predictive value of NOTCH1 mutations reached marginal statistical significance (HR, 0.42; 95% CI, 0.17–1.04; P = 0.059). The median of TMB for NOTCH1-mutant tumors was significantly higher than that for NOTCH1-WT tumors, and GSEA revealed that NOTCH1 mutations manifested various defects in the repair of DNA damage. NOTCH1-mutant tumors displayed an inflamed tumor microenvironment (TME), manifesting as increased PD-L1 expression and tumor-infiltrating CD8+ T cells. Conclusion NOTCH1 mutations define a molecular subtype of NSCLC, which are more common in smokers and patients with SCC, are characterized with higher TMB, inflamed TME, and display improved survival of ICB therapy for NSCLC patients.
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来源期刊
CiteScore
16.50
自引率
0.00%
发文量
7
审稿时长
16 weeks
期刊介绍: Immuno Targets and Therapy is an international, peer-reviewed open access journal focusing on the immunological basis of diseases, potential targets for immune based therapy and treatment protocols employed to improve patient management. Basic immunology and physiology of the immune system in health, and disease will be also covered.In addition, the journal will focus on the impact of management programs and new therapeutic agents and protocols on patient perspectives such as quality of life, adherence and satisfaction.
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