In a study that longitudinally profiled the gut microbiome in a multicentre cohort of 175 patients with advanced melanoma undergoing immune checkpoint blockade (ICB), through Bayesian regression models with higher-order interactions, the researchers characterised microbiome changes in patients with progression-free survival (PFS) ≥12 or PFS <12 months during ICB, including in different clinical contexts such as treatment regimen, development of colitis and proton-pump inhibitor (PPI) use.
The study underlines the dynamic nature of the gut microbiome and indicates that longitudinal profiling at finer taxonomic resolution in association with host factors is critical for guiding microbiome-targeted interventions aimed at improving treatment outcomes according to Drs. Johannes R. Björk and Rinse K. Weersma of the Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen in Groningen, the Netherlands, and colleagues who published the findings on 16 February 2024 in the Nature Medicine.
The authors wrote in the background that cross-sectional studies have assessed the gut microbiome before ICB initiation, but the field is hampered by a lack of consensus as different studies often report different microbial biomarkers of response. Despite the lack of a thorough understanding of underlying mechanisms, multiple microbiome-directed clinical trials are ongoing, including foecal microbiota transplantation (FMT). To better interpret the findings from these trials and to increase understanding of gut microbiome dynamics more generally and in the context of ICB, there is an urgent need for longitudinal microbiome studies along the course of ICB treatment.
In the article published in the Nature Medicine, the authors described the profiling of the gut microbiome via shotgun metagenomics followed by MetaPhlAn4 and microbial metabolic (MetaCyc) analyses at four time points during the first 12 weeks of treatment in a multicentre cohort comprising 175 patients treated with ICB for advanced melanoma.
The authors hypothesised that many microbial abundances may increase or decrease over the treatment period because patients received an immunotherapy infusion at each study visit. Furthermore, because baseline abundances of several microbial taxa have already been shown to differ between ICB response and nonresponse, they also hypothesised that patients responding and not responding to the treatment exhibit different patterns of microbial increase/decrease.
To model this, the authors used a Bayesian regression model with higher-order interactions, allowing patients with PFS ≥12 months and patients with PFS <12 months to exhibit different longitudinal (linear) trajectories for each microbial feature. While they focused on the overall comparison between patients with PFS ≥12 and PFS <12 months averaging over the effect of multiple confounders, the methodology also allowed to analyze microbial dynamics between patients with PFS ≥12 and PFS <12 months in three relevant clinical scenarios: treatment regimen (mono versus combination ICB), the development of ICB-induced colitis, and concomitant PPI use. The latter two have well-studied effects on the gut microbiome.
The study team showed that several microbial species-level genome bins (SGBs) and pathways exhibit distinct patterns from baseline in patients achieving PFS ≥12 versus patients with PFS <12 months. Out of 99 SGBs that could discriminate between these two groups, 20 were differentially abundant only at baseline, while 42 were differentially abundant only after treatment initiation. The study team identified five and four SGBs that had consistently higher abundances in patients with PFS ≥12 and <12 months. Constructing a log ratio of these SGBs, they found an association with overall survival.
The study team also found different microbial dynamics in different clinical contexts including the type of ICB regimen, development of immune-related adverse events and concomitant medication use.
Insights into the longitudinal dynamics of the gut microbiome in association with host factors and treatment regimens will be critical for guiding rational microbiome-targeted therapies aimed at enhancing ICB efficacy. These findings provide an important roadmap for designing and interpreting microbiome-based intervention studies. To further validate the findings and move the clinical gut microbiome field forward from a biomarker perspective to actionable treatments, continued efforts should go into longitudinal profiling of patients undergoing treatment with ICB at larger scales, linking the gut microbiome, metabolome and immunome to treatment outcome.
This work was supported by the Seerave Foundation. The work was also supported by the European Research Council, MIUR ‘Futuro in Ricerca’ grant, the European Horizon 2020 programme, the National Cancer Institute of the US National Institutes of Health grant, the Premio Internazionale Lombardia e Ricerca 2019, the Spanish Fondo de Investigaciones Sanitarias grants of the Instituto de Salud Carlos III, Spain, co-financed by European Development Regional Fund, the Wellcome Trust grant, the Dutch Cancer Society grant, and the Leeds group was supported by the Medical Research Council grant.
The authors thank the team of the NGS Core Facility at University of Trento for support in sample preparation and for metagenomic sequencing and the high-performance computing team at the University of Trento. They also thank Oncobiome and the Institut Gustave Roussy for their involvement and support of the initiative. The collection of samples from the Hospital Clínic in Barcelona was funded by grant from Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III, Spain.
Reference
Björk JR, Bolte LA, Thomas AM, et al. Longitudinal gut microbiome changes in immune checkpoint blockade-treated advanced melanoma. Nature Medicine; Published online 16 February 2024. DOI: https://doi.org/10.1038/s41591-024-02803-3