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Characterizations of multi-kingdom gut microbiota in immune checkpoint inhibitor-treated hepatocellular carcinoma
Chengpei Zhu1,2, Chenchen Zhang3, Shanshan Wang1
1Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Beijing, China.
Background:
The association between gut bacteria and the response to immune checkpoint inhibitors (ICI) in hepatocellular carcinoma (HCC) has been studied; however, multi-kingdom gut microbiome alterations and interactions in ICI-treated HCC cohorts are not fully understood.
Methods:
From November 2018 to April 2022, patients receiving ICI treatment for advanced HCC were prospectively enrolled. Herein, we investigated the multi-kingdom microbiota characterization of the gut microbiome, mycobiome, and metabolome using metagenomic, ITS2, and metabolomic data sets of 80 patients with ICI-treated HCC.
Results:
Our findings demonstrated that bacteria and metabolites differed significantly between the durable clinical benefit (DCB) and non-durable clinical benefit (NDB) groups, whereas the differences were smaller for fungi. The overall diversity of bacteria and fungi before treatment was higher in the DCB group than in the NDB group, and the difference in diversity began to change with the use of immunotherapy after 6-8 weeks. We also explored the alterations of gut microbes in the DCB and NDB groups, established 18 bacterial species models as predictive biomarkers for predicting whether immunotherapy is of sustained benefit (area under the curve=75.63%), and screened two species of bacteria (Actinomyces_sp_ICM47, and Senegalimassilia_anaerobia) and one metabolite (galanthaminone) as prognostic biomarkers for predicting survival in patients with HCC treated with ICI.
Conclusions:
In this study, the status and characterization of the multi-kingdom microbiota, including gut bacteria, fungi, and their metabolites, were described by multiomics sequencing for the first time in patients with HCC treated with ICI. Our findings demonstrate the potential of bacterial taxa as predictive biomarkers of ICI clinical efficacy, and bacteria and their metabolites as prognostic biomarkers.
Insights
This study reveals that gut bacteria and metabolites significantly impact immune checkpoint inhibitor (ICI) treatment response in liver cancer. Specific bacterial species and metabolites can predict treatment success and patient survival.
Area of Science:
- Microbiology
- Immunology
- Oncology
Background:
- The gut microbiome's role in immune checkpoint inhibitor (ICI) response for hepatocellular carcinoma (HCC) is recognized, but multi-kingdom microbial interactions remain unclear.
- Understanding these complex interactions is crucial for optimizing ICI therapy in HCC patients.
Purpose of the Study:
- To characterize the multi-kingdom gut microbiota (bacteria, fungi) and metabolome in patients with advanced HCC undergoing ICI treatment.
- To identify microbial and metabolic biomarkers predictive of durable clinical benefit (DCB) and prognostic of survival.
Main Methods:
- Prospective enrollment of 80 patients with advanced HCC receiving ICI treatment (November 2018 - April 2022).
- Multi-kingdom microbiota analysis using metagenomic sequencing (bacteria), ITS2 sequencing (fungi), and metabolomic profiling.
- Comparative analysis between durable clinical benefit (DCB) and non-durable clinical benefit (NDB) groups.
Main Results:
- Significant differences in bacteria and metabolites were observed between DCB and NDB groups; fungal differences were less pronounced.
- Higher bacterial and fungal diversity pre-treatment was associated with DCB.
- Developed 18 bacterial species models predicting sustained immunotherapy benefit (AUC=75.63%) and identified specific bacteria and a metabolite as prognostic biomarkers for survival.
Conclusions:
- This study provides the first multiomics characterization of the multi-kingdom microbiota and metabolome in ICI-treated HCC patients.
- Bacterial taxa show potential as predictive biomarkers for ICI efficacy.
- Gut bacteria and their metabolites serve as promising prognostic biomarkers for survival in HCC patients treated with ICI.
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