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

ObjectiveProgrammed 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.DesignSyngeneic 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.ResultsWe 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.ConclusionOur 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.

FDX1 can Impact the Prognosis and Mediate the Metabolism of Lung Adenocarcinoma

“…Metabolism plays an important role in carcinogenesis, and in recent years, it has been leveraged for tumor treatments (Biswas, 2015;Vander Heiden and DeBerardinis, 2017;Kumar and Misra, 2019). Multiple studies have shown that metabolism and cancer are closely related; currently, metabolites are important targets in the treatment of cancer (Chae and Kim, 2018;Dinges et al, 2019;Huang et al, 2021). The mitochondria electron transport chain locates in the inner membrane of the mitochondria and is composed of four complexes, including complexes I, II, III, and ATP synthase (Chen and Butow, 2005).…”

Wound Healing Effect of Gintonin Involves Lysophosphatidic Acid Receptor/Vascular Endothelial Growth Factor Signaling Pathway in Keratinocytes

“…Korean ginseng, a root of Panax ginseng C.A. Meyer, contains various biologically active components such as ginsenosides, polysaccharides, and glycolipoproteins [1,9,10]. In a previous study, we isolated a glycolipoprotein called gintonin from ginseng and found that gintonin has a variety of components including ginseng major latex-like protein151 (GLP151), ginseng ribonuclease-like storage protein, phosphatidic acids, and lysophosphatidic acid (LPA) [11].…”

Strategies for Remodeling the Tumor Microenvironment Using Active Ingredients of Ginseng—A Promising Approach for Cancer Therapy

“…With regard to cancer, a recent study showed that oral ginseng polysaccharides combined with anti-PD-1-mAb could improve therapeutic sensitivity of anti-PD-1-mAb in patients with NSCLC. This effect may have been related to ginseng polysaccharides-induced remodeling of gut microbiota structure in chemotherapeutic non-responders that led to increased abundance of metabolites, such as short-chain fatty acids (SCFAs), while also down-regulating IDO activity ( Huang et al, 2021 ). Thus, the immunosuppressive TME associated with NSCLC was altered, leading to heightened immunotherapeutic sensitivity induced by ginseng polysaccharides administration.…”

“…Recent studies have shown that ginseng polysaccharides enhanced the anti-tumor response triggered by anti-PD-1 mAb by increasing CD8 + T cell function and decreasing Treg inhibition. These effects may have been due to effects of ginseng polysaccharides on tryptophan metabolism that acted to reshape the gut microbiota that resulted in significantly increased production of L-tryptophan and decreased production of L-kynurenine and IDO expression in tumor cells ( Huang et al, 2021 ). In conclusion, ginsenosides and ginseng polysaccharides appear to enhance the adaptive immune response against tumor cells, warranting further study ( Figure 2 ).…”