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Gut microbiota and metabolites associate with outcomes of immune checkpoint inhibitor–treated unresectable hepatocellular carcinoma
Pei‐Chang Lee (National Yang Ming Chiao Tung University, Taipei Veterans General Hospital), Chi-Jung Wu (National Yang Ming Chiao Tung University, Taipei Veterans General Hospital), Ya‐Wen Hung (National Yang Ming Chiao Tung University, Taipei Veterans General Hospital), Chieh Ju Lee (Taipei Veterans General Hospital), Chen‐Ta Chi (National Yang Ming Chiao Tung University, Taipei Veterans General Hospital), I‐Cheng Lee (National Yang Ming Chiao Tung University, Taipei Veterans General Hospital), Yu‐Lun Kuo, Shih-Hsuan Chou, Jiing–Chyuan Luo (National Yang Ming Chiao Tung University, Taipei Veterans General Hospital), Ming‐Chih Hou (National Yang Ming Chiao Tung University, Taipei Veterans General Hospital), Yi‐Hsiang Huang (National Yang Ming Chiao Tung University, Taipei Veterans General Hospital)
Résumé : Background Immune checkpoint inhibitors (ICIs) are promising agents for unresectable hepatocellular carcinoma (uHCC), but lack effective biomarker to predict outcomes. The gut microbiome can modulate tumor response to immunotherapy, but its effect on HCC remains unclear. Methods From May 2018 to February 2020, patients receiving ICI treatment for uHCC were prospectively enrolled; their fecal samples were collected before treatment. The fecal microbiota and metabolites were analyzed from 20 patients with radiology-proven objective responses (OR) and 21 randomly selected patients with progressive disease (PD). After March 2020, 33 consecutive Child-Pugh-A patients were recruited as a validation cohort. Additionally, feces from 17 healthy volunteers were collected for comparison of background microbes. Results A significant dissimilarity was observed in fecal bacteria between patients with OR and patients with PD before immunotherapy. Prevotella 9 was enriched in patients with PD, whereas Lachnoclostridium, Lachnospiraceae, and Veillonella were predominant in patients with OR. Ursodeoxycholic acid and ursocholic acid were significantly enriched in the feces of patients with OR and strongly correlated with the abundance of Lachnoclostridium . The coexistence of Lachnoclostridium enrichment and Prevotella 9 depletion significantly predicted better overall survival (OS). In the validation cohort, better progression-free survival (PFS) and OS were noted in patients who had a preferable microbial signature in comparison with counter-group (PFS: 8.8 months vs 1.8 months; OS: not reached vs 6.5 months, both p<0.001). Conclusions Fecal microbiota and bile acids were associated with outcomes of immunotherapy for uHCC. These findings highlight the potential role of gut microbiota and metabolites as biomarkers to predict outcomes of ICI-treated HCC.