Gut Microbiome Diversity and Specific Composition During Immunotherapy in Japanese Responders with Non-Small Cell Lung Cancer

Abstract Cancer immunotherapy including immune checkpoint inhibitors (ICI) has revolutionized non-small cell lung cancer (NSCLC) therapy. Recently, the microbiome status before initiation of ICI therapy has been emphasized as a predictive biomarker in patients undergoing ICI therapy. However, the microbiome diversity and composition during ICI therapy is unknown. This multicenter, prospective observational study analyzed both saliva and feces from 28 patients with NSCLC. We performed 16S ribosomal RNA gene sequencing, then analyzed associations of oral and gut microbiome diversity or composition with ICI response. Seventeen patients (responders) had a partial ICI response, and the remaining 11 patients (non-responders) had stable or progressive disease. At the genus level, the alpha diversity of the gut microbiome was significantly greater in ICI responders than in non-responders (Chao 1, p = 0.0174; PD whole tree, p = 0.0219; observed species, p = 0.0238; Shannon, p = 0.0362), while the beta diversity of the gut microbiome was significantly lower in ICI responders (principal coordinates analysis, p = 0.035). Compositional differences in the gut microbiome were observed between the two groups; in particular, Blautia was enriched in ICI responders, whereas RF32 unclassified was enriched in ICI non-responders. There were no significant differences between groups in the oral microbiome. This study revealed a strong association between gut microbiome diversity and ICI response in Japanese NSCLC patients. Moreover, specific gut microbiome compositions may influence the ICI response. These findings might be useful in identifying biomarkers to predict ICI response, as well as in developing biotic therapies to enhance the ICI response.