Intestinal Akkermansia muciniphila predicts clinical response to PD-1 blockade in advanced non-small cell lung cancer patients

Aside from PD-L1 expression, biomarkers of response to immune checkpoint inhibitors (ICI) in non-small cell lung cancer (NSCLC) are needed. We previously reported in 100 NSCLC and kidney cancer patients that fecal Akkermansia muciniphila (Akk) correlated with ICI clinical success. The endpoint of this study was to prospectively validate the prognostic significance of fecal Akk in advanced NSCLC patients treated with first or second line ICI. We performed shotgun metagenomics-based microbiome profiling using two different pipelines in 338 NSCLC patients. Baseline stool Akk was associated with increased objective response rates and overall survival in multivariate analyses, independent of PD-L1 expression, antibiotics and performance status. Intestinal Akk was accompanied by a richer commensalism, including Eubacterium hallii and Bifidobacterium adolescentis and a more inflamed tumor microenvironment in a subset of patients. However, antibiotic use (20% of cases) coincided with a relative dominance of Akk above 4.8% accompanied with the genus Clostridium, both associated with resistance to ICI. Our study shows significant differences in relative abundance of Akk that could be useful for future studies as a tool to aid patient stratification.