Genomics guiding personalized first-line immunotherapy response in lung and bladder tumors.

IF 6.1 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Jenifer Brea-Iglesias, María Gallardo-Gómez, Ana Oitabén, Martin E Lázaro-Quintela, Luis León, Joao M Alves, Manuel Pino-González, Laura Juaneda-Magdalena, Carme García-Benito, Ihab Abdulkader, Laura Muinelo, Jesús M Paramio, Mónica Martínez-Fernández
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引用次数: 0

Abstract

Background: Immune checkpoint inhibitors (ICI) have revolutionized cancer treatment, particularly in advanced non-small cell lung cancer (NSCLC) and muscle-invasive bladder cancer (MIBC). However, identifying reliable predictive biomarkers for ICI response remains a significant challenge. In this study, we analyzed real-world cohorts of advanced NSCLC and MIBC patients treated with ICI as first-line therapy.

Methods: Tumor samples underwent Whole Genome Sequencing (WGS) to identify specific somatic variants and assess tumor mutational burden (TMB). Additionally, mutational signature extraction and pathway enrichment analyses were performed to uncover the underlying mechanisms of ICI response. We also characterized HLA-I haplotypes and investigated LINE-1 retrotransposition.

Results: Distinct mutation patterns were identified in patients who responded to treatment, suggesting potential biomarkers for predicting ICI effectiveness. In NSCLC, tumor mutational burden (TMB) did not differ significantly between responders and non-responders, while in MIBC, higher TMB was linked to better responses. Specific mutational signatures and HLA haplotypes were associated with ICI response in both cancers. Pathway analysis showed that NSCLC responders had active inflammatory and immune pathways, while pathways enriched in non-responders related to FGFR3 and neural crest differentiation, associated to resistance mechanisms. In MIBC, responders had alterations in DNA repair, leading to more neoantigens and a stronger ICI response. Importantly, for the first time, we found that LINE-1 activation was positively linked to ICI response, especially in MIBC.

Conclusion: These findings reveal promising biomarkers and mechanistic insights, offering a new perspective on predicting ICI response and opening up exciting possibilities for more personalized immunotherapy strategies in NSCLC and MIBC.

基因组学指导肺和膀胱肿瘤的个体化一线免疫治疗反应。
背景:免疫检查点抑制剂(ICI)已经彻底改变了癌症治疗,特别是晚期非小细胞肺癌(NSCLC)和肌肉浸润性膀胱癌(MIBC)。然而,确定ICI反应的可靠预测生物标志物仍然是一个重大挑战。在这项研究中,我们分析了以ICI作为一线治疗的晚期NSCLC和MIBC患者的现实世界队列。方法:对肿瘤样本进行全基因组测序(WGS),鉴定特异性体细胞变异,评估肿瘤突变负荷(TMB)。此外,还进行了突变特征提取和途径富集分析,以揭示ICI反应的潜在机制。我们还鉴定了hla -1单倍型,并研究了LINE-1反转录转位。结果:在对治疗有反应的患者中发现了不同的突变模式,这提示了预测ICI有效性的潜在生物标志物。在NSCLC中,肿瘤突变负担(TMB)在应答者和无应答者之间没有显著差异,而在MIBC中,更高的TMB与更好的应答相关。特异性突变特征和HLA单倍型与两种癌症的ICI反应相关。通路分析显示,NSCLC应答者具有活跃的炎症和免疫通路,而与FGFR3和神经嵴分化相关的非应答者的通路则丰富,与耐药机制相关。在MIBC中,应答者的DNA修复发生改变,导致更多的新抗原和更强的ICI应答。重要的是,我们首次发现LINE-1激活与ICI反应呈正相关,特别是在MIBC中。结论:这些发现揭示了有希望的生物标志物和机制见解,为预测ICI反应提供了新的视角,并为NSCLC和MIBC的更个性化的免疫治疗策略开辟了令人兴奋的可能性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Journal of Translational Medicine
Journal of Translational Medicine 医学-医学:研究与实验
CiteScore
10.00
自引率
1.40%
发文量
537
审稿时长
1 months
期刊介绍: The Journal of Translational Medicine is an open-access journal that publishes articles focusing on information derived from human experimentation to enhance communication between basic and clinical science. It covers all areas of translational medicine.
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