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

Jumin Huang(Macau University of Science and Technology), Di Liu(Chinese Academy of Sciences), Yuwei Wang(Macau University of Science and Technology), Liang Liu(Macau University of Science and Technology), Jian Li(Sun Yat-sen University), Jing Yuan(Capital Institute of Pediatrics), Zhi‐Hong Jiang(Macau University of Science and Technology), Zebo Jiang(Macau University of Science and Technology), W.L. Wendy Hsiao(Macau University of Science and Technology), Haizhou Liu(Chinese Academy of Sciences), Imran Khan(Macau University of Science and Technology), Ying Xie(Macau University of Science and Technology), Jian‐Lin Wu(Macau University of Science and Technology), Ya‐Jia Xie(Macau University of Science and Technology), Yizhong Zhang(Macau University of Science and Technology), Yu Fu(Macau University of Science and Technology), Junyi Liao(Macau University of Science and Technology), Wenjun Wang(Macau University of Science and Technology), Huanling Lai(Macau University of Science and Technology), Axi Shi(Macau University of Science and Technology), Jun Cai(Macau University of Science and Technology), Lianxiang Luo(Guangdong Medical College), Runze Li(Macau University of Science and Technology), Xiaojun Yao(Macau University of Science and Technology), Xing‐Xing Fan(Macau University of Science and Technology), Qibiao Wu(Macau University of Science and Technology), Zhongqiu Liu(Guangzhou University of Chinese Medicine), Peiyu Yan(Macau University of Science and Technology), Jing‐Guang Lu(Macau University of Science and Technology), Ming-Rong Yang(Macau University of Science and Technology), Lin Wang(Macau University of Science and Technology), Yabing Cao(Kiang Wu Hospital), Hong Wei(Sun Yat-sen University), Elaine Lai‐Han Leung(Macau University of Science and Technology)
Gut
May 18, 2021
10.1136/gutjnl-2020-321031
Cited by 504Open Access
Full Text

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 T eff 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.

Related Papers

No related papers found

Powered by citation graph analysis