Multi-omics of the gut microbial ecosystem in the immunotherapy resistance in microsatellite instability-high gastrointestinal cancer patients

ABSTRACT: Despite the encouraging efficacy of anti-PD-1/PD-L1 immunotherapy in microsatellite instability-high/deficient mismatch repair (MSI-H/dMMR) advanced gastrointestinal cancer, many patients exhibit primary or acquired resistance. Using multi-omics approaches, we interrogated gut microbiome, blood metabolome and cytokines/chemokines of MSI-H/dMMR gastrointestinal cancer patients (N = 77) at baseline and during the treatment. We identified a number of microbes (e.g. Porphyromonadaceae) and metabolites (e.g. arginine) highly associated with primary resistance to immunotherapy. An independent validation cohort (N = 40) and mouse model were used to further confirm our findings. A predictive machine learning model for primary resistance was also built and achieved an accuracy of 0.79 on the external validation set. Furthermore, several microbes were pinpointed which gradually changed during the process of acquired resistance. In summary, our study demonstrated the essential role of gut microbiome in drug resistance, and this could be utilized as a preventative diagnosis tool and therapeutic targets in the future.

INSTRUMENT(S): Liquid Chromatography MS - negative - reverse phase, Liquid Chromatography MS - positive - reverse phase

PROVIDER: MTBLS9021 | MetaboLights | 2026-07-16

REPOSITORIES: MetaboLights