The Gut Microbiome Associates with Immune Checkpoint Inhibition Outcomes in Patients with Advanced Non–Small Cell Lung Cancer

Abstract

The gut microbiome (GM) plays an important role in shaping systemic immune responses and influences immune checkpoint inhibitor (ICI) efficacy. Antibiotics worsen clinical outcomes in patients receiving ICI. However, whether GM profiling and baseline antibiotic can be a biomarker of ICI efficacy in advanced non–small cell lung cancer (NSCLC) remains unknown. We prospectively collected baseline (pre-ICI) fecal samples and clinical data of 70 Japanese patients suffering from advanced NSCLC and treated them with anti–PD-1/PD-L1 antibodies as a first-line or treatment-refractory therapy. We performed 16S rRNA V3–V4 sequencing of gene amplicons of fecal samples, and bacteria diversity and differential abundance analysis was performed. The clinical endpoints were objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and immune-related adverse events (irAE). ORR was 34%, and median PFS and OS were 5.2 and 16.2 months, respectively. Patients who received pre-ICI antibiotic had lower alpha diversity at baseline and underrepresentation of Ruminococcaceae UCG 13 and Agathobacter. When analyzing antibiotic-free patients, alpha diversity correlated with OS. In addition, Ruminococcaceae UCG 13 and Agathobacter were enriched in patients with favorable ORR and PFS >6 months. Ruminococcaceae UCG 13 was enriched in patients with OS >12 months. GM differences were observed between patients who experienced low- versus high-grade irAE. We demonstrated the negative influence of antibiotic on the GM composition and identified the bacteria repertoire in patients experiencing favorable responses to ICI. See articles by Tomita et al., p. 1236, and Peng et al., p. 1251

Network Analysis of Gut Microbiome and Metabolome to Discover Microbiota-Linked Biomarkers in Patients Affected by Non-Small Cell Lung Cancer

“…Interestingly, likewise to the role of the GM in other cancers, recent findings also indicate a relationship between the GM and the lungs [15]. Moreover, there is growing evidence demonstrating the association of the GM and its metabolome in ICI treatment response in NSCLC [16][17][18][19]. Indeed, not only the microbial cells but also their metabolites play a role in the stimulation of the immune response [5].…”

Tumor-Associated Microbiome: Where Do We Stand?

“…Accumulating data indicates that tumor responses to chemotherapies such as gemcitabine [ 38 ] and cyclophosphamide [ 126 ] depend on the gut microbiome. Several studies have shown a correlation between the gut microbiome composition and diversity and the efficacy of immunotherapy in patients with different tumor types, including melanoma, renal clear cell carcinoma, and lung cancer [ 4 , 15 , 17 , 127 , 128 , 129 , 130 ]. Recent data from melanoma patients revealed that the administration of stools from responders to immune checkpoint inhibitors (ICI) to non-responders can revert the primary resistance to these agents and lead to increased tumor infiltration by CD8 T cells [ 131 ], as previously suggested in pre-clinical studies [ 127 ].…”

Analysis of the Gut Microbiota: An Emerging Source of Biomarkers for Immune Checkpoint Blockade Therapy in Non-Small Cell Lung Cancer

“…Moreover, the impact of the microbiota on cancer and cancer treatment is an emerging area of great interest [ 26 , 27 ]. In the era of novel immune-modulating agents, differential composition of the gut microbiota has been studied as one of the variables accounting for interpatient heterogeneity in ICB responses [ 28 , 29 , 30 , 31 , 32 ]. Additionally, lung cancer patients are frequently treated with antibiotics (ATB) and this intervention could modify or unbalance the gut microbiota.…”