Ginseng polysaccharides alter the gut microbiota and kynurenine/tryptophan ratio, potentiating the antitumour effect of antiprogrammed cell death 1/programmed cell death ligand 1 (anti-PD-1/PD-L1) immunotherapy.

Abstract

OBJECTIVE:

Programmed death 1 and its ligand 1 (PD-1/PD-L1) immunotherapy is promising for late-stage lung cancer treatment, however, the response rate needs to be improved. Gut microbiota plays a crucial role in immunotherapy sensitisation and Panax ginseng has been shown to possess immunomodulatory potential. In this study, we aimed to investigate whether the combination treatment of ginseng polysaccharides (GPs) and αPD-1 monoclonal antibody (mAb) could sensitise the response by modulating gut microbiota.

DESIGN:

Syngeneic mouse models were administered GPs and αPD-1 mAb, the sensitising antitumour effects of the combination therapy on gut microbiota were assessed by faecal microbiota transplantation (FMT) and 16S PacBio single-molecule real-time (SMRT) sequencing. To assess the immune-related metabolites, metabolomics analysis of the plasma samples was performed.

RESULTS:

We found GPs increased the antitumour response to αPD-1 mAb by increasing the microbial metabolites valeric acid and decreasing L-kynurenine, as well as the ratio of Kyn/Trp, which contributed to the suppression of regulatory T cells and induction of Teff cells after combination treatment. Besides, the microbial analysis indicated that the abundance of Parabacteroides distasonis and Bacteroides vulgatus was higher in responders to anti-PD-1 blockade than non-responders in the clinic. Furthermore, the combination therapy sensitised the response to PD-1 inhibitor in the mice receiving microbes by FMT from six non-responders by reshaping the gut microbiota from non-responders towards that of responders.

CONCLUSION:

Our results demonstrate that GPs combined with αPD-1 mAb may be a new strategy to sensitise non-small cell lung cancer patients to anti-PD-1 immunotherapy. The gut microbiota can be used as a novel biomarker to predict the response to anti-PD-1 immunotherapy.

• Authors: Jumin Huang, Di Liu, Yuwei Wang, Liang Liu, Jian Li, Jing Yuan, Zhihong Jiang, Zebo Jiang, Wl Wendy Hsiao, Haizhou Liu, Imran Khan, Ying Xie, Jianlin Wu, Yajia Xie, Yizhong Zhang, Yu Fu, Junyi Liao, Wenjun Wang, Huanling Lai, Axi Shi, Jun Cai, Lianxiang Luo, Runze Li, Xiaojun Yao, Xingxing Fan, Qibiao Wu, Zhongqiu Liu, Peiyu Yan, Jingguang Lu, Mingrong Yang, Lin Wang, Yabing Cao, Hong Wei, Elaine Lai-Han Leung
• Journal: Gut (Gut) Vol. 71 Issue 4 Pg. 734-745 (04 2022) ISSN: 1468-3288 [Electronic] England
• PMID: 34006584 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Chemical References

• Antibodies, Monoclonal
• B7-H1 Antigen
• Immunologic Factors
• Ligands
• Polysaccharides
• Kynurenine
• Tryptophan

Topics

• Animals
• Antibodies, Monoclonal (pharmacology)
• Apoptosis
• B7-H1 Antigen (metabolism)
• Carcinoma, Non-Small-Cell Lung (therapy)
• Cell Death
• Gastrointestinal Microbiome (physiology)
• Humans
• Immunologic Factors (pharmacology)
• Immunotherapy (methods)
• Kynurenine (pharmacology)
• Ligands
• Lung Neoplasms (therapy)
• Mice
• Panax (metabolism)
• Polysaccharides (pharmacology)
• Tryptophan (pharmacology)