Cross-cohort gut microbiome associations with immune checkpoint inhibitor response in advanced melanoma
AuthorsLee, K. A.
Thomas, A. M.
Bolte, L. A.
Björk, J. R.
de Ruijter, L. K.
Leeming, E. R.
Shaw, H. M.
de Vries, E. G. E.
Fehrmann, R. S. N.
Hospers, G. A. P.
Spector, T. D.
Weersma, R. K.
AffiliationDepartment of Twin Research and Genetic Epidemiology, King's College London, London, UK. Department CIBIO, University of Trento, Trento, Italy. Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen, the Netherlands. Department of Medical Oncology, University of Groningen and University Medical Center Groningen, Groningen, the Netherlands. Department of Oncology, Lancashire Teaching Hospitals NHS Trust, Preston, UK. Dermatology Department, Hospital Clínic Barcelona, Universitat de Barcelona, IDIBAPS, Barcelona, Spain. Centro de Investigación Biomédica en Red en Enfermedades Raras, Instituto de Salud Carlos III, Barcelona, Spain. U1015 INSERM, University Paris Saclay, Gustave Roussy Cancer Center and Oncobiome Network, Villejuif-Grand-Paris, France. Molecular Oncology Group, CRUK Manchester Institute, University of Manchester, Manchester, UK. Division of Haematology and Immunology, Institute of Medical Research at St. James's, University of Leeds, Leeds, UK. Biochemical and Molecular Genetics Department, Hospital Clínic de Barcelona, IDIBAPS and University of Barcelona, Barcelona, Spain. Department of Medical Oncology, Guys Cancer Centre, Guys and St Thomas's NHS Trust, London, UK. The Christie NHS Foundation Trust, Manchester, UK. Division of Cancer Sciences, University of Manchester, Manchester, UK. European Institute of Oncology (Istituto Europeo di Oncologia, IRCSS), Milan, Italy. Department of Medical Oncology, Mount Vernon Cancer Centre, Northwood, UK. Rheumatology & Orthopaedics Division, School of Medicine, University of Nottingham, Nottingham, UK. Graduate School of Public Health and Health Policy, City University of New York, New York, NY, USA. Department of Dermatology, Mount Vernon Cancer Centre, Northwood, UK. Department of Twin Research and Genetic Epidemiology, King's College London, London, UK. firstname.lastname@example.org. Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen, the Netherlands. email@example.com. Department CIBIO, University of Trento, Trento, Italy. firstname.lastname@example.org. European Institute of Oncology (Istituto Europeo di Oncologia, IRCSS), Milan, Italy. email@example.com.
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CitationThe 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.
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