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.

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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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