e16165 Background: Immunotherapy with checkpoint inhibitors (ICI) is a promising treatment for unresectable hepatocellular carcinoma (HCC), but lack of effective biomarker to predict treatment response. Gut microbiome could modulate tumor response to immunotherapy in melanoma; but its effects on HCC are still unclear. Methods: From May 2018 to April 2020, 94 patients received ICI treatment for unresectable HCC (uHCC) in Taipei Veterans General Hospital, the feces samples were prospectively collected before ICI treatment. Finally, 20 patients with radiology proven objective tumor responses (OR; 3 complete responses and 17 partial responses) following immunotherapy, and 21 randomly selected patients with progressive disease (PD) were enrolled for fecal microbiota and metabolites investigation. In addition, feces from 17 healthy volunteers were taken as normal control. Results: Although the alpha diversity was not significantly different among groups, the principal component analysis of Bray-Curtis distance showed a significant clustering of fecal microbiota between HCC patients and healthy volunteers. The significant bacterial dissimilarity was observed between OR and PD patients following immunotherapy (p = 0.016 and 0.019 by Anoism and Adonis tests, respectively). According to linear discriminant analysis (LDA) effect size (LEfSe), a prominence of Prevotella usually regarded as a pathogenic bacterium, was more abundant in HCC patients with PD to ICI treatment. While Veillonella, Lachnospiraceae, Lachnoclostridium, Lactobacillales, Streptococcaceae and Ruminococcaceae were predominant in patients with OR (LDA score [log10] > 3). In addition, primary bile acids, including murocholic acid, α and β-muricholic acids, and secondary bile acids, including ursodeoxycholic acid, ursocholic acid, tauro-ursodeoxycholic acid, and taurohyocholic acid were significantly dominant in the feces of patients with OR to ICI treatment. Correlation network analysis in patients with OR showed significant linkages between Lachnoclostridium, Ruminococcus and secondary bile acids. Conclusions: Fecal microbiota and bile acids are associated with the response to immunotherapy for uHCC patients. These findings highlight the potential role of microbiota as a biomarker and strategy to enhance response to immunotherapy by modifying gut microbiota for uHCC.
Downstaging and Resection of Initially Unresectable Hepatocellular Carcinoma with Tyrosine Kinase Inhibitor and Anti-PD-1 Antibody Combinations
