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4bases’ Paper of the Month – April 2022 – Cross-cohort gut microbiome associations with ICIs response in advanced melanoma

Our team’s reading recommendation for this month goes to “Cross-cohort gut microbiome associations with immune checkpoint inhibitor response in advanced melanoma”[1] by Lee KA et al., an extremely interesting paper just published in “Nature Medicine”.

Immune Checkpoint Inhibitors are used in cancer immunotherapy, in particular in the treatment of metastatic melanomas for which several drugs – monoclonal antibodies – are approved and therefore commercially available. The clinical response to these ICIs is obviously variable but it interestingly seems to be influenced by the composition of the gut microbiome, although there is limited consensus on the specific microbiome characteristics linked to their clinical benefits. 

The published study’s objective was to get to a better understanding of the relationship between the composition of the gut microbiome, as determined by metagenomic sequencing of stool samples, and response to ICIs as determined by treatment outcomes. The idea behind this being the validation of the fact that the gut microbiome could be a potential biomarker of response, as well as a therapeutic target. 

175 patients, from five distinct cohorts (3 in UK, 1 in the Netherlands and 1 in Spain) with unresectable stage III and stage IV cutaneous melanoma who received ICI treatment after collecting stool samples were recruited and, on another hand, the study integrated data from 147 patients belonging to published melanoma cohorts. This study is the largest metagenomic study to date to identify gut microbiome associations with ICI response.

Several assessment methods were applied for the evaluation of the treatment outcome (comprehensive clinical data, standardized radiological response assessments (RECIST v1.1) and biological specimens were collected before treatment and longitudinally at each cycle of treatment) and All samples were subjected to shot- gun metagenomic sequencing at an average sequencing depth of 7.74 Gb, and the 165 samples that passed strict quality control were analyzed at the taxonomic and functional potential levels using bioBakery 3, a set of computational methods for the analysis of microbial communities. Machine learning analyses were performed. 

The link between the microbiome and overall response rates (ORRs) and progression-free survival (PFS) with ICIs was confirmed but, at the same time, a limited reproducibility of microbiome-based signatures across cohorts was revealed. 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. The role of the human gut microbiome in ICI response appears therefore more complex than previously thought, as it extends beyond differing microbial species simply present or absent in responders and nonresponders.

Further research is certainly needed, but, as concluded by the authors, “This study improves the current understanding of the link between the gut microbiome and ICI response and sheds light on the complexities of microbiome science in human disease.”  

We at 4bases proudly support research and contribute to the development of new molecular diagnostic tools for the metagenomic sequencing of stool samples and a better understanding of the gut microbioma and the way it interacts with other biological mechanisms. 

[1] Lee KA, Thomas AM, Bolte LA, Björk JR, de Ruijter LK, Armanini F, Asnicar F, Blanco-Miguez A, Board R, Calbet-Llopart N, Derosa L, Dhomen N, Brooks K, Harland M, Harries M, Leeming ER, Lorigan P, Manghi P, Marais R, Newton-Bishop J, Nezi L, Pinto F, Potrony M, Puig S, Serra-Bellver P, Shaw HM, Tamburini S, Valpione S, Vijay A, Waldron L, Zitvogel L, Zolfo M, de Vries EGE, Nathan P, Fehrmann RSN, Bataille V, Hospers GAP, Spector TD, Weersma RK, Segata N. Cross-cohort gut microbiome associations with immune checkpoint inhibitor response in advanced melanoma. Nat Med. 2022 Mar;28(3):535-544. doi: 10.1038/s41591-022-01695-5. Epub 2022 Feb 28. PMID: 35228751.


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