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Integrative stratification of response to immunotherapy using host and microbial signatures in patients with advanced non-small cell lung cancer
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DOI：10.1186/s13073-026-01736-5.png)
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Abstract
En 中文
The gut microbiome has been linked to responses to immune checkpoint inhibitors (ICIs), yet longitudinal multi-omics studies remain limited. Here, we serially collected gut microbiome data and performed multi-omics analyses, including RNA sequencing (RNA-seq) and whole-exome sequencing (WES), on samples from 92 patients with advanced non-small cell lung cancer (NSCLC) treated with pembrolizumab, to identify factors contributing to treatment response. We compared gut microbiome data with those of a healthy cohort (n = 92) and examined changes in gut microbial signatures during immunotherapy. Gut microbiome data from publicly available ICI-treated cohorts (n = 728) were also used together with our own cohort to develop and validate a score for classifying response to ICIs. Responders (defined as complete response, partial response, or stable disease of at least 6 months) were enriched for Faecalibacterium, while non-responders were enriched for Lactobacillus and Escherichia, with these taxa showing specific associations with dietary fiber intake and antibiotic use. Dynamic shifts in dysbiotic signatures were observed throughout treatment and disease progression, with dissimilarity from the healthy cohort decreasing after treatment only in responders but increasing at progression in both responders and non-responders. We also developed a cross-population score based on the ratio of responder- to non-responder-associated microbial markers. This score showed a significant positive correlation with the index reflecting gut microbial health status and improved response stratification when combined with tumor mutational burden (TMB). These findings highlight the importance of characterizing dysbiosis using gut microbial signatures, which act along a distinct and complementary axis to explain responses to ICIs.
Keywords:
Gut microbiome
Immune checkpoint inhibitors
Non-small cell lung cancer
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