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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 HuangDr Neher’s Biophysics Laboratory for Innovative Drug Discovery/State Key laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macau, ChinaDi LiuComputational Virology Group, Center for Bacteria and Virus Resources and Application, Wuhan Institute of Virology Chinese Academy of Sciences, Wuhan, Hubei, ChinaYuwei WangDr Neher’s Biophysics Laboratory for Innovative Drug Discovery/State Key laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macau, ChinaLiang LiuDr Neher’s Biophysics Laboratory for Innovative Drug Discovery/State Key laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macau, ChinaJian LiPrecision Medicine Institute, Sun Yat-sen University First Affiliated Hospital, Guangzhou, Guangdong, ChinaJing YuanDepartment of Bacteriology, Capital Institute of Pediatrics, Chaoyang District, Beijing, ChinaZhi‐Hong JiangDr Neher’s Biophysics Laboratory for Innovative Drug Discovery/State Key laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macau, ChinaZebo JiangDr Neher’s Biophysics Laboratory for Innovative Drug Discovery/State Key laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macau, ChinaW.L. Wendy HsiaoDr Neher’s Biophysics Laboratory for Innovative Drug Discovery/State Key laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macau, ChinaHaizhou LiuWuhan Institute of VirologyImran KhanDr Neher’s Biophysics Laboratory for Innovative Drug Discovery/State Key laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macau, ChinaYing XieDr Neher’s Biophysics Laboratory for Innovative Drug Discovery/State Key laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macau, ChinaJian‐Lin WuDr Neher’s Biophysics Laboratory for Innovative Drug Discovery/State Key laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macau, ChinaYa‐Jia XieDr Neher’s Biophysics Laboratory for Innovative Drug Discovery/State Key laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macau, ChinaYizhong ZhangDr Neher’s Biophysics Laboratory for Innovative Drug Discovery/State Key laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macau, ChinaYu FuDr Neher’s Biophysics Laboratory for Innovative Drug Discovery/State Key laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macau, ChinaJunyi LiaoDr Neher’s Biophysics Laboratory for Innovative Drug Discovery/State Key laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macau, ChinaWenjun WangDr Neher’s Biophysics Laboratory for Innovative Drug Discovery/State Key laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macau, ChinaHuanling LaiDr Neher’s Biophysics Laboratory for Innovative Drug Discovery/State Key laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macau, ChinaAxi ShiDr Neher’s Biophysics Laboratory for Innovative Drug Discovery/State Key laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macau, ChinaJun CaiDr Neher’s Biophysics Laboratory for Innovative Drug Discovery/State Key laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macau, ChinaLianxiang LuoThe Marine Biomedical Research Institute, Guangdong Medical University, Zhanjiang, Guangdong, ChinaRunze LiDr Neher’s Biophysics Laboratory for Innovative Drug Discovery/State Key laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macau, ChinaXiaojun YaoDr Neher’s Biophysics Laboratory for Innovative Drug Discovery/State Key laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macau, ChinaXing‐Xing FanDr Neher’s Biophysics Laboratory for Innovative Drug Discovery/State Key laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macau, ChinaQibiao WuDr Neher’s Biophysics Laboratory for Innovative Drug Discovery/State Key laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macau, ChinaZhongqiu LiuJoint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People’s Republic of China, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, ChinaPeiyu YanDr Neher’s Biophysics Laboratory for Innovative Drug Discovery/State Key laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macau, ChinaJing‐Guang LuDr Neher’s Biophysics Laboratory for Innovative Drug Discovery/State Key laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macau, ChinaMing-Rong YangDr Neher’s Biophysics Laboratory for Innovative Drug Discovery/State Key laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macau, ChinaLin WangDr Neher’s Biophysics Laboratory for Innovative Drug Discovery/State Key laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macau, ChinaYabing CaoDepartment of Oncology, Kiang Wu Hospital, Macau, Macau, ChinaHong WeiPrecision Medicine Institute, Sun Yat-sen University First Affiliated Hospital, Guangzhou, Guangdong, ChinaElaine Lai‐Han LeungDr Neher’s Biophysics Laboratory for Innovative Drug Discovery/State Key laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macau, China

2021en

ABI

Annotatsiya

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.

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DOI: 10.1136/gutjnl-2020-321031

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