Gut microbial species and metabolic pathways associated with response to treatment with immune checkpoint inhibitors in metastatic melanoma

Abstract

In patients with metastatic cancer, gut microbiome composition differs between responder and non-responders to immune checkpoint inhibitors. However, there is little consensus on the microbiome taxa associated with response or lack of response. Additionally, recognized confounders of gut microbiome composition have generally not been taken into account. In this study, metagenomic shotgun sequencing was performed on freshly frozen pre-treatment stool samples from 25 patients (12 responders and 13 non-responders) with unresectable metastatic melanoma treated with immune checkpoint inhibitors. We observed no significant differences in alpha-diversity and bacterial prevalence between responders and non-responders (P > 0.05). In a zero-inflated multivariate analysis, correcting for important confounders such as age, BMI and use of antibiotics, 68 taxa showed differential abundance between responders and non-responders (false-discovery rate < 0.05). Cox-regression analysis showed longer overall survival for carriers of Streptococcus parasanguinis [hazard ratio (HR): 6.9] and longer progression-free survival for carriers of Bacteroides massiliensis (HR: 3.79). In contrast, carriership of Peptostreptococcaceae (unclassified species) was associated with shorter overall survival (HR 0.18) and progression-free survival (HR 0.11). Finally, 17 microbial pathways differentially abundant between responder and non-responders were observed. These results underline the association between gut microbiome composition and response to immune checkpoint inhibitor therapy in a cohort of patients with cutaneous melanoma.