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Cross-cohort gut microbiome associations with immune checkpoint inhibitor response in advanced melanoma
Karla A Lee1, Andrew Maltez Thomas2, Laura A Bolte3
1Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.
Abstract:
The composition of the gut microbiome has been associated with clinical responses to immune checkpoint inhibitor (ICI) treatment, but there is limited consensus on the specific microbiome characteristics linked to the clinical benefits of ICIs. We performed shotgun metagenomic sequencing of stool samples collected before ICI initiation from five observational cohorts recruiting ICI-naive patients with advanced cutaneous melanoma (n = 165). Integrating the dataset with 147 metagenomic samples from previously published studies, we found that the gut microbiome has a relevant, but cohort-dependent, association with the response to ICIs. A machine learning analysis confirmed the link between the microbiome and overall response rates (ORRs) and progression-free survival (PFS) with ICIs but also revealed limited reproducibility of microbiome-based signatures across cohorts. Accordingly, a panel of species, including Bifidobacterium pseudocatenulatum, Roseburia spp. and Akkermansia muciniphila, associated with responders was identified, but no single species could be regarded as a fully consistent biomarker across studies. Overall, the role of the human gut microbiome in ICI response appears more complex than previously thought, extending beyond differing microbial species simply present or absent in responders and nonresponders. Future studies should adopt larger sample sizes and take into account the complex interplay of clinical factors with the gut microbiome over the treatment course.
Insights
The gut microbiome influences response to immune checkpoint inhibitors (ICIs), but specific microbial biomarkers are not consistently reproducible across studies. Research suggests a complex interplay beyond simple species presence or absence for predicting ICI treatment success.
Area of Science:
- Microbiome research
- Immunotherapy
- Oncology
Background:
- Gut microbiome composition is linked to immune checkpoint inhibitor (ICI) treatment response.
- Limited consensus exists on specific microbiome features predicting clinical benefits from ICIs.
- Understanding these associations is crucial for optimizing cancer immunotherapy.
Purpose of the Study:
- To investigate the association between gut microbiome composition and clinical response to ICIs in advanced cutaneous melanoma.
- To identify reproducible microbiome-based signatures predictive of overall response rates (ORRs) and progression-free survival (PFS).
- To explore the complexity of the gut microbiome's role in ICI treatment efficacy.
Main Methods:
- Shotgun metagenomic sequencing of stool samples from 165 ICI-naive patients with advanced cutaneous melanoma.
- Integration with 147 previously published metagenomic datasets.
- Machine learning analysis to identify links between microbiome features and clinical outcomes (ORRs, PFS).
Main Results:
- A relevant, yet cohort-dependent, association between the gut microbiome and ICI response was observed.
- Machine learning confirmed the link to ORRs and PFS, but microbiome signatures showed limited cross-cohort reproducibility.
- Specific species like Bifidobacterium pseudocatenulatum, Roseburia spp., and Akkermansia muciniphila were associated with responders, but no single species served as a consistent biomarker.
Conclusions:
- The human gut microbiome's role in ICI response is complex and extends beyond the presence or absence of specific microbial species.
- Current microbiome-based signatures for predicting ICI response lack consistent reproducibility across different patient cohorts.
- Future research requires larger sample sizes and consideration of clinical factors and longitudinal microbiome changes during treatment.
