Cross-cohort gut microbiome associations with immune checkpoint inhibitor response in advanced melanoma

Karla A Lee, Andrew Maltez Thomas, Laura A Bolte, Johannes R Björk, Laura Kist de Ruijter, Federica Armanini, Francesco Asnicar, Aitor Blanco-Miguez, Ruth Board, Neus Calbet-Llopart, Lisa Derosa, Nathalie Dhomen, Kelly Brooks, Mark Harland, Mark Harries, Emily R Leeming, Paul Lorigan, Paolo Manghi, Richard Marais, Julia Newton-BishopLuigi Nezi, Federica Pinto, Miriam Potrony, Susana Puig, Patricio Serra-Bellver, Heather M Shaw, Sabrina Tamburini, Sara Valpione, Amrita Vijay, Levi Waldron, Laurence Zitvogel, Moreno Zolfo, Elisabeth G E de Vries, Paul Nathan, Rudolf S N Fehrmann, Véronique Bataille, Geke A P Hospers, Tim D Spector*, Rinse K Weersma*, Nicola Segata*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

12 Citations (Scopus)
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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.

Original languageEnglish
Pages (from-to)535–544
Number of pages28
JournalNature Medicine
Volume28
Early online date28-Feb-2022
DOIs
Publication statusPublished - Mar-2022

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