Gut microbiota predictive of the efficacy of consolidation immunotherapy and chemoradiotherapy toxicity in lung cancer

BACKGROUND: Gut microbiota (GM) predict responses to immune checkpoint inhibitors (ICIs) in patients with advanced lung cancer. However, its role in patients with locally advanced lung cancer undergoing chemoradiotherapy (CRT) combined with consolidation ICIs remains unclear. METHODS: A total of 177 fecal samples were collected pre- and post-CRT. Using 16S ribosomal RNA (16S rRNA) sequencing and metagenomic data from an internal cohort and published studies, the kinetics of microbiota were analyzed using the Wilcoxon signed-rank test, while prognostic factors for progression-free survival (PFS) were identified using Cox regression modeling and machine learning algorithms. FINDINGS: The GM configuration was unaffected by traditional CRT. However, in cases of CRT with consolidation ICIs, patients with long-PFS showed a higher alpha diversity at baseline, followed by a reduction during treatment, contrasting with the stable diversity observed in the short-PFS group. Enrichment of the symbiotic microbe Akkermansia muciniphila (Akk) after CRT was observed, with its increased abundance correlating with extended distant metastasis-free survival in patients undergoing CRT with consolidation ICIs. Notably, the trend in Akk variation was a prognostic indicator of survival outcomes in patients undergoing CRT combined with ICIs. GM was also involved in the development of treatment-related pneumonia and was a promising predictive marker for severe pneumonia. CONCLUSIONS: CRT with consolidation ICIs has more pronounced effects on the GM than CRT alone in patients with locally advanced lung cancer. The dynamic variation in Akk has predictive potential for patient survival in this context. FUNDING: This study was supported by the National Science and Technology Major Project.