Gut microbiota and metabolites associate with outcomes of immune checkpoint inhibitor-treated unresectable hepatocellular carcinoma

Pei-Chang Lee; Chi-Jung Wu; Ya-Wen Hung; Chieh Ju Lee; Chen-Ta Chi; I-Cheng Lee; Kuo Yu-Lun; Shih-Hsuan Chou; Jiing-Chyuan Luo; Ming-Chih Hou; Yi-Hsiang Huang

doi:10.1136/jitc-2022-004779

Gut microbiota and metabolites associate with outcomes of immune checkpoint inhibitor-treated unresectable hepatocellular carcinoma

J Immunother Cancer. 2022 Jun;10(6):e004779. doi: 10.1136/jitc-2022-004779.

Authors

Pei-Chang Lee^{1

2}, Chi-Jung Wu^{1

2

3}, Ya-Wen Hung^{1

2}, Chieh Ju Lee¹, Chen-Ta Chi^{1

2

3}, I-Cheng Lee^{1

2}, Kuo Yu-Lun⁴, Shih-Hsuan Chou⁴, Jiing-Chyuan Luo^{1

2

5}, Ming-Chih Hou^{1

2}, Yi-Hsiang Huang^{6

2

3}

Affiliations

¹ Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
² School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.
³ Institute of Clinical Medicine, Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.
⁴ Biotools Co. Ltd, New Taipei City, Taiwan.
⁵ Healthcare and Services Center, Taipei Veterans General Hospital, Taipei, Taiwan.
⁶ Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan yhhuang@vghtpe.gov.tw.

Abstract

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.

Keywords: immunotherapy; liver neoplasms.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Carcinoma, Hepatocellular* / drug therapy
Gastrointestinal Microbiome*
Humans
Immune Checkpoint Inhibitors* / therapeutic use
Liver Neoplasms* / drug therapy
Treatment Outcome

Substances

Immune Checkpoint Inhibitors