Gut microbiome-driven modulation of the tumor immune microenvironment optimizes dual checkpoint blockade in advanced non-small-cell lung cancer.

High gut microbiota diversity was associated with improved progression-free survival and overall survival in patients receiving ipilimumab plus nivolumab (I-N) alone.

• This was a prospective study enrolling 50 patients with advanced NSCLC treated with I-N with or without chemotherapy.
• Gut microbiota diversity was assessed from fecal samples collected before treatment initiation.
• The association between high gut microbiota diversity and improved outcomes was observed specifically in the I-N alone subgroup.
• The association between gut microbiota diversity and treatment efficacy was not observed in patients treated with I-N plus chemotherapy.

High gut microbiota diversity was associated with greater CD8+ tumor-infiltrating lymphocyte (TIL) infiltration, particularly PD-1+CD8+ TILs.

• Tumor-infiltrating lymphocytes were evaluated using multiplex immunofluorescence staining.
• The association was specifically noted for PD-1+CD8+ TILs, suggesting an activated or exhausted CD8+ T cell phenotype relevant to checkpoint blockade response.
• This finding links gut microbiome composition to the tumor immune microenvironment.

Responders receiving I-N alone showed enrichment of short-chain fatty acid (SCFA)-producing bacteria, which were linked to favorable metabolic pathways associated with antitumor immune responses.

• SCFA-producing bacteria were enriched specifically in responders treated with I-N alone, not in the chemotherapy combination group.
• These bacteria were associated with favorable metabolic pathways connected to antitumor immune responses.
• Objective response rate was among the outcomes analyzed alongside gut microbiota characteristics.

Antibiotic use before treatment initiation was independently associated with shorter progression-free survival and overall survival across all treatment regimens.

• This association was observed across all treatment regimens, including both I-N alone and I-N plus chemotherapy.
• Antibiotic use was identified as an independent predictor of worse outcomes, suggesting it was assessed in a multivariate analysis.
• This finding was consistent regardless of whether patients received chemotherapy alongside dual checkpoint blockade.

Baseline gut microbiota diversity may help identify patients more likely to have improved outcomes with I-N plus chemotherapy compared to I-N alone.

• Patients with low baseline gut microbiota diversity may represent a subgroup in whom adding chemotherapy to dual checkpoint blockade provides greater benefit.
• This finding suggests gut microbiota profiling could contribute to treatment selection and personalized medicine strategies in NSCLC.
• The study highlights the potential of gut microbiota as a novel biomarker for dual checkpoint blockade in NSCLC.