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
Open accessAbstract
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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Written from the paper’s full text.
TL;DR
Ginseng polysaccharides (GPs) combined with αPD-1 mAb potentiated antitumour responses in mouse lung cancer models by increasing CD8+ T cell function and reducing Tregs, alongside altered gut microbiota and tryptophan/kynurenine metabolism. In a small clinical cohort, responders to pembrolizumab had distinct gut microbiota, and GPs plus αPD-1 mAb reinstated responses in germ-free mice transplanted with non-responder faeces.
Key findings
- Combination GPs plus αPD-1 mAb suppressed tumour growth in LLC-bearing mice: on day 24, 75.2% and 65.1% tumour growth suppression versus Vehicle and αPD-1 mAb alone, respectively, with prolonged survival.
- Combination treatment increased CD8+/CD4+ T cell ratio and CD8+ T cell production of IFN-γ, TNF-α and GZMB, while reducing FoxP3+ regulatory T cells in periphery and tumour.
- GPs plus αPD-1 mAb increased plasma valeric acid and decreased L-kynurenine and the kynurenine/tryptophan ratio, with lower IDO expression in tumours; in vitro fermentation of human faeces with GPs increased L-tryptophan and reduced L-kynurenine and Kyn/Trp under aerobic and anaerobic conditions.
- Among 16 Chinese NSCLC patients treated with anti-PD-1 blockade, 10 were responders and 6 non-responders; responders showed higher alpha diversity and enrichment of Parabacteroides distasonis (p=0.04), bacterium LF-3 (p=0.02) and Sutterella wadsworthensis HGA0223 (p=0.09), with Bacteroides vulgatus top-ranked in responders. FMT from six non-responders into germ-free mice produced resistance to αPD-1 mAb, but GPs plus αPD-1 mAb reinstated response and increased B. vulgatus and P. distasonis.
Methods
- Syngeneic mouse models: C57BL/6J and humanised PD-1 knock-in mice inoculated with Lewis lung cancer or B16-F10 cells; 24 mice divided into Vehicle, αPD-1 mAb (250 µg/mouse, five injections at 3-day intervals), GPs (200 mg/kg daily oral) and combination groups.
- Faecal microbiota transplantation from six clinical non-responders into germ-free mice, followed by tumour inoculation and GPs/αPD-1 mAb treatment; 16S PacBio SMRT sequencing of mouse and patient faecal samples; UPLC-MS plasma metabolomics for SCFAs, L-kynurenine and L-tryptophan; flow cytometry, immunohistochemistry and RNA-sequencing of intraepithelial lymphocytes.
- Clinical sample: 16 Chinese NSCLC patients treated with anti-PD-1 blockade (pembrolizumab), classified as 10 responders and 6 non-responders; baseline faecal samples analysed. Statistical analyses included ANOVA, Mann-Whitney U test, Kruskal-Wallis test, LEfSe and log-rank tests.
Limitations
- The paper does not state a dedicated limitations section.
- Evident from the text: the mechanistic and efficacy findings are primarily from mouse models, and the clinical microbiota comparison is a small observational cohort (16 patients; 10 responders, 6 non-responders) without a human intervention testing GPs.
- Evident from the text: the FMT experiment used faecal samples from only six non-responders, and the authors note that whether B. vulgatus and P. distasonis are key orchestrators of resistance to PD-1 inhibitors requires further investigation.
Model-written summary. Check it against the paper before relying on it.
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Claims the paper makes
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- Findingown data
Combination treatment with GPs and αPD-1 mAb significantly prolonged survival of LLC-bearing mice.
“Correspondingly, the survival of mice was significantly prolonged (figure 1D).”
Quote in the paperSubstantial claim - Findingown data
Ginseng polysaccharides (GPs) potentiated the antitumour effect of an anti-PD-1 monoclonal antibody (αPD-1 mAb) in Lewis lung cancer (LLC)-bearing mice.
“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.”
- Also stated in: § Combination therapy sensitises the antitumour effect of αPD-1 mAb in tumour-bearing mouse models · plain
“After combination treatment, the conventional LLC-bearing mice exhibited an increased response to αPD-1 mAb and reduced tumour progression (online supplemental figure 1A).”
- Also stated in: § Combination therapy sensitises the antitumour effect of αPD-1 mAb in tumour-bearing mouse models · plain
“On day 24, the combination treatment group exhibited 75.2% and 65.1% tumour growth suppression compared with the Vehicle and αPD-1mAb treatment alone group, respectively.”
Quote in the paperSubstantial claim - Also stated in: § Combination therapy sensitises the antitumour effect of αPD-1 mAb in tumour-bearing mouse models · plain
- Findingown data
In LLC-bearing germ-free mice transplanted with faecal microbiota from non-responders, treatment with GPs plus αPD-1 mAb reinstated the response.
“Interestingly, when mice were treated with GPs plus αPD-1 mAb, the response was reinstated.”
Quote in the paperSubstantial claim - Findingown data
The Kyn/Trp ratio in plasma decreased after combination treatment in mice.
“we determined the content of tryptophan and kynurenine in mice plasma and found Kyn/Trp ratio decreased after combination treatment (figure 6J).”
Quote in the paperSubstantial claim - Findingown data
The combination treatment of GPs plus αPD-1 mAb significantly delayed tumour growth in these mice.
“The combination treatment significantly delayed tumour growth (figure 6B).”
Quote in the paperSubstantial claim
- Findingown data
IDO expression in tumour tissues was lower after combination treatment.
“Consistently, we also observed a lower IDO expression in tumour tissues after combination treatment (figure 6K, L).”
Quote in the paperSubstantial claim - Findingown data
Combination treatment increased production of IFN-γ, TNF-α and GZMB among CD8+ T cells in peripheral and tumour tissues.
“The production of functional cytokines, IFN-γ, TNF-α andGZMB among CD8+ T cells also increased both in peripheral and tumour tissues (figure 2B–D, (online supplemental figure 2), indicating the beneficial effect of the drug combination.”
Quote in the paperSubstantial claim - Findingown data
Combination therapy sensitised the response to PD-1 inhibitor in mice receiving microbes by faecal microbiota transplantation (FMT) from six non-responders by reshaping the gut microbiota from non-responders towards that of responders.
“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.”
- Also stated in: § What are the new findings? · plain
“Combination therapy with GPs and αPD-1 mAb reshaped the composition of the gut microbiota from non-responders towards that of the responders, which reinstated the response to the αPD-1 mAb in mice transplanted with PD-1 non-responder faecal samples.”
Quote in the paperSubstantial claim - Also stated in: § What are the new findings? · plain
- Findingown data
GPs combined with αPD-1 mAb increased the SCFA-producing bacteria Muribaculum in LLC tumour-bearing mice.
“In the present study, we first observed that GPs combined with αPD-1 mAb could increase the SCFA-producing bacteria, Muribaculum to sensitise the antitumour effect of αPD-1 mAb in the LLC tumour-bearing mice.”
- Also stated in: § Discussion · plain
“Combination treatment enriched the abundance of Muribaculum when administrated into LLC-bearing mice.”
Quote in the paperSubstantial claim - Also stated in: § Discussion · plain
- Findingown data
In Chinese patients with NSCLC treated with anti-PD-1 blockade, baseline gut microbiome alpha diversity (richness and evenness) was higher in responders than in non-responders.
“The alpha diversity of the gut microbiome suggested that the richness and evenness of the Rs were higher than those of the NRs (figure 5A).”
Quote in the paperSubstantial claim - Findingown data
IDO expression in tumour tissues was downregulated in the combination group.
“we performed IHC staining and found the expression of IDO in the combination group was downregulated (figure 4K).”
Quote in the paperSubstantial claim - Findingown data
In intraepithelial lymphocytes (IELs), combination treatment upregulated intraepithelial protection genes (CLCA3, Zg16, Pla2g10, Agr2, Guca2a, Tff3), metabolism-related genes (Dgat2, Ces2a) and S100A6 compared with αPD-1 mAb alone.
“Compared with that in the αPD-1 mAb alone group, the expression of intraepithelial protection genes (CLCA3, Zg16, Pla2g10, Agr2, Guca2a and Tff3),28–30 metabolism-related genes (Dgat2 and Ces2a)31 32 and S100A6 was significantly upregulated in the combination treatment group.”
Quote in the paperNot a substantial claim - Findingown data
In the authors' initial study, GPs potentiated the antitumour effect of αPD-1 mAb in LLC-bearing mice.
“In our initial study, we found that GPs potentiated the antitumour effect of αPD-1 mAb in LLC-bearing mice.”
Quote in the paperSubstantial claim - Findingown data
The abundance of Muribaculaceae increased in the GP group compared with the Vehicle group.
“We also observed the increase of Muribaculaceae when compared GP and Vehicle group (online supplemental figure 3)”
Quote in the paperSubstantial claim - Findingown data
Combination treatment downregulated FoxP3+ regulatory T (Treg) cells in peripheral and tumour tissues.
“Meanwhile, we also observed the downregulation of FoxP3+ regulatory T (Treg) cells in peripheral and tumour tissues (figure 2E).”
Quote in the paperSubstantial claim - Findingown data
The abundance of these bacteria (B. vulgatus, P. distasonis, bacterium LF-3, Sutterella wadsworthensis HGA0223) was increased in patients who had better response and survival rates.
“Interestingly, the abundance of these bacteria was increased in patients who had better response and survival rates.”
Quote in the paperSubstantial claim - Findingown data
Sutterella wadsworthensis HGA0223 was overrepresented in responders compared with non-responders (p=0.09).
“Sutterella wadsworthensis HGA0223 (p=0.09”
Quote in the paperNot a substantial claim - Findingown data
Valerate was significantly increased after cotreatment with GPs and αPD-1 mAb compared with treatment with αPD-1 mAb alone.
“In particular, valerate, which is commonly low in the plasma, was increased significantly after cotreatment with GPs and αPD-1 mAb compared with treatment with αPD-1 mAb alone.”
Quote in the paperSubstantial claim - Findingown data
Bacterium LF-3 was overrepresented in responders compared with non-responders (p=0.02).
“bacterium LF-3 (p=0.02)”
Quote in the paperNot a substantial claim - Findingown data
In the combination group, the abundance of Bacteroides, especially B. vulgatus and P. distasonis, was significantly increased compared with αPD-1 mAb and Vehicle groups.
“we found in combination group, the abundance of Bacteroides, especially B. vulgatus and P. distasonis were significantly increased when compared with αPD-1 mAb and Vehicle group, respectively (figure 6M, O”
- Also stated in: § Discussion · plain
“we found the abundance of B. vulgatus and P. distasonis were significantly increased after combination treatment compared with αPD-1 mAb or Vehicle group, respectively.”
- Also stated in: § Discussion · plain
“A rich abundance of B. vulgatus and P. distasonis were found in combination group by 16S PacBio SMRT sequencing compared with αPD-1 mAb and vehicle group.”
Quote in the paperSubstantial claim - Also stated in: § Discussion · plain
- Findingown data
Valeric acid abundance was significantly increased in the combination treatment group compared with the αPD-1 mAb alone group.
“notably, the abundance of valeric acid was significantly increased in the combination treatment group compared with αPD-1 mAb alone group (figure 4A–G).”
Quote in the paperSubstantial claim - Findingown data
Combination treatment reduced the infiltration of inflammatory cells in the colon.
“histopathological evaluation of the colon revealed that the combination treatment could reduce the infiltration of inflammatory cells in the colon (figure 3E, F).”
Quote in the paperNot a substantial claim - Findingown data
The abundance of Parabacteroides distasonis and Bacteroides vulgatus was higher in responders to anti-PD-1 blockade than in non-responders in the clinic.
“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.”
Quote in the paperSubstantial claim - Findingown data
Germ-free mice transplanted with faecal microbiota from non-responders were resistant to αPD-1 mAb treatment, similar to non-responders.
“As expected, similarly to the NRs, we found that mice were resistant to αPD-1 mAb treatment.”
Quote in the paperSubstantial claim - Findingown data
Combination treatment increased the CD8+/CD4+ ratio in peripheral blood, spleen and tumour tissues compared with αPD-1 mAb alone.
“We observed that CD8+/CD4+ ratio in the combinational group increased in both peripheral (blood and spleen tissues) and tumour tissues when compared with αPD-1 mAb alone group (figure 2A).”
Quote in the paperSubstantial claim - Findingown data
At the species level, the relative abundance of Bacteroides vulgatus was the highest in responders.
“At the species level, we observed that the relative abundance of Bacteroides vulgatus accounts for the top of the list in Rs”
- Also stated in: § Discussion · plain
“The results revealed enrichment of B. vulgatus and P. distasonis in Rs.”
- Also stated in: § Discussion · plain
“16S SMRT sequencing found Parabacteroides distasonis and Bacteroides vulgatus were higher in abundance in responders to pembrolizumab.”
Quote in the paperNot a substantial claim - Also stated in: § Discussion · plain
- Findingown data
When compared with the GP alone group, immune response-related genes were upregulated in the combination group.
“When compared with GP alone group, we observed that the immune response-rated genes were upregulated in the combination group (figure 3I, J).”
Quote in the paperNot a substantial claim - Findingown data
In IELs, combination treatment downregulated immunoglobulin variable region heavy and light chain genes, Igkv4-68, Lrrk2, Camsap2, Myo5a, Bmf, Slc29a3, and Mios compared with αPD-1 mAb alone.
“Conversely, the expression of immunoglobulin variable region heavy chain genes (Ighv1-64, Ighv6-6, Ighv5-4, Ighv1-55, Ighv1-50 and Ighv1-26), immunoglobulin variable region light chain genes (Iglv2), immunoglobulin kappa variable genes (Igkv4-68), Lrrk2, Camsap2, Myo5a, Bmf, Slc29a3, and Mios was downregulated in the IELs from mice treated with combination therapy (figure 3G).”
Quote in the paperNot a substantial claim - Findingown data
In this study, all SCFAs including propionate, butyrate, isobutyrate, valerate, isovalerate and hexanoate increased after treatment with αPD-1 mAb.
“In this study, we also observed that all the SCFAs including propionate, butyrate, isobutyrate, valerate, isovalerate and hexanoate, increased after treatment with αPD-1 mAb.”
Quote in the paperNot a substantial claim - Findingown data
Parabacteroides distasonis was overrepresented in responders compared with non-responders (p=0.04).
“an overrepresentation of three gut microbes: Parabacteroides distasonis (p=0.04)”
- Also stated in: § Discussion · plain
“The results revealed enrichment of B. vulgatus and P. distasonis in Rs.”
- Also stated in: § Discussion · plain
“16S SMRT sequencing found Parabacteroides distasonis and Bacteroides vulgatus were higher in abundance in responders to pembrolizumab.”
Quote in the paperSubstantial claim - Also stated in: § Discussion · plain
- Findingown data
NSCLC responders and non-responders to pembrolizumab exhibited distinct gut microbiota diversity as detected by 16S PacBio SMRT sequencing.
“NSCLC responders and non-responders to pembrolizumab exhibited distinct gut microbiota diversity as detected by 16S PacBio SMRT sequencing, and two differentially abundant species, Parabacteroides distasonis and Bacteroides vulgatus were found.”
Quote in the paperSubstantial claim - Findingown data
The abundance of all measured short-chain fatty acids (SCFAs) increased after treatment with αPD-1 mAb except for acetic acid.
“Interestingly, we found that the abundance of all the SCFAs increased after treatment with αPD-1 mAb except for acetic acid”
Quote in the paperSubstantial claim - Findingown data
Antibiotic treatment compromised the antitumour efficacy in LLC-bearing mice.
“we evaluated the tumour growth in LLC-bearing mice treated with antibiotics and found antibiotic treatment compromised the antitumour efficacy (figure 3C, D).”
Quote in the paperSubstantial claim - Findingown data
Gene ontology (GO) analysis revealed that the differentially expressed IEL genes were mainly associated with the lysosome, secretory granule and energy metabolism.
“Gene ontology (GO) analysis revealed that these differentially expressed genes were mainly associated with the lysosome, secretory granule and energy metabolism, which can protect the integrity of the gut barrier (figure 3H).”
Quote in the paperNot a substantial claim - Findingnone given
Combination treatment upregulated expression of epithelium protecting genes including CLCA3, TFF3, AGR2, Zg16, Pla2g10, and Guca2a.
“Combination treatment upregulated the expression of epithelium protecting genes, like CLCA3, TFF3, AGR2, Zg16, Pla2g10 and Guca2a.”
Quote in the paperNot a substantial claim - Findingreasoning
The peripheral Treg population decreased in response to the reduction in kynurenine.
“Additionally, the peripheral Treg population decreased in response to the reduction in kynurenine.”
Quote in the paperSubstantial claim - Findingown data
In vitro fermentation of human faecal samples from healthy donors with GPs increased tryptophan and reduced kynurenine levels under both aerobic and anaerobic conditions.
“We in vitro fermented human faecal samples from healthy donors with GPs and found an increase in tryptophan and a reduction in kynurenine levels under both aerobic and anaerobic conditions.”
Quote in the paperSubstantial claim - Findingown data
IDO activity was decreased in GF mice transferred microbiota from NRs.
“We also observed the decreased IDO activity in GF mice transferred microbiota from NRs.”
Quote in the paperSubstantial claim - Findingown data
Compared with αPD-1 mAb treatment alone, combination treatment led to a reduced Kyn/Trp ratio by reducing kynurenine but not tryptophan in mice.
“In addition, compared with αPD-1 mAb treatment alone, combination treatment led to a reduced Kyn/Trp ratio by reducing kynurenine but not tryptophan in mice.”
Quote in the paperSubstantial claim - Premisecitation
The response rate of non-small cell lung cancer (NSCLC) patients to anti-PD-1 immunotherapy is less than 25%.
“The response rate of non-small cell lung cancer (NSCLC) patients to anti-PD-1 immunotherapy is less than 25%”
- Also stated in: § Introduction · plain
“However, even though these biomarkers were used as the gold standard, the response rate (<25%) is still unsatisfactory, even leading to hyperprogressive disease (HPD).7 8”
Quote in the paperSubstantial claim0 of 1 sources checked- cites 7 8
Not checked in the free run.
- Also stated in: § Introduction · plain
- Premisecitation
Increased SCFAs point to longer progression-free survival time.
“These results suggest that increased SCFAs point to longer progression-free survival time.40”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [40] Nomura, 2019, Association of SCFA in gut microbiome and clinical response in solid cancer patients treated with andi-PD-1 antibody, Ann Oncol source
Not checked in the free run.
- Interpretationown data
GPs combined with αPD-1 mAb may be a new strategy to sensitise non-small cell lung cancer patients to anti-PD-1 immunotherapy.
“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.”
Quote in the paperSubstantial claim - Interpretationown data
The combination treatment may reshape gut microbiota from non-responders towards that of responders to sensitise the response to αPD-1 mAb treatment.
“These results indicated that the combination treatment may reshape gut microbiota from NRs towards that of Rs to sensitise the response to αPD-1 mAb treatment.”
Quote in the paperSubstantial claim - Interpretationown data
GPs can sensitise the response to αPD-1 mAb in LLC-bearing mice.
“Collectively, these data revealed that GPs can sensitise the response to αPD-1 mAb in LLC-bearing mice.”
Quote in the paperSubstantial claim - Interpretationown data
GPs may have the potential to enrich the abundance of Muribaculaceae.
“which indicated that GPs may have the potential to enrich the abundance of Muribaculaceae.”
Quote in the paperSubstantial claim - Interpretationown data
Reduction of FoxP3+ Tregs by GPs plus αPD-1 mAb may contribute to preventing hyperprogressive disease (HPD).
“In our study, GPs combined with αPD-1 mAb reduced the proportion of FoxP3+ Tregs both in the periphery and tumour, which may contribute to preventing HPD.”
Quote in the paperSubstantial claim - Premisecitation
Specific gut bacteria, including Bacteroides fragilis, Bacteroides thetaiotaomicron, Bifidobacterium, Akkermansia muciniphila and Faecalibacterium spp., have favourable responses to cancer immunotherapy in preclinical tumour models and patients with cancer.
“Such as Bacteroides fragilis, Bacteroides thetaiotaomicron, Bifidobacterium, Akkermansia muciniphila and Faecalibacterium spp. have been shown to have favourable responses to cancer immunotherapy in both preclinical tumour models and patients with cancer.12–15”
Quote in the paperSubstantial claim0 of 4 sources checked - Interpretationown data
Combination treatment may be associated with IDO activity.
“The results indicated that combination treatment may be associated with IDO activity.”
Quote in the paperSubstantial claim - Interpretationown data
The lysosome, secretory granule and energy metabolism functions associated with the differentially expressed IEL genes can protect the integrity of the gut barrier.
“Gene ontology (GO) analysis revealed that these differentially expressed genes were mainly associated with the lysosome, secretory granule and energy metabolism, which can protect the integrity of the gut barrier (figure 3H).”
Quote in the paperNot a substantial claim - Premisecitation
In solid cancer patients treated with nivolumab, faecal SCFA abundance was higher in responders than non-responders.
“Nomura et al observed that the abundance of faecal SCFAs in solid cancer patients treated with nivolumab was higher in R than NR.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [40] Nomura, 2019, Association of SCFA in gut microbiome and clinical response in solid cancer patients treated with andi-PD-1 antibody, Ann Oncol source
Not checked in the free run.
- Interpretationown data
The gut microbiota can be used as a novel biomarker to predict the response to anti-PD-1 immunotherapy.
“The gut microbiota can be used as a novel biomarker to predict the response to anti-PD-1 immunotherapy.”
- Also stated in: § How might it impact on clinical practice in the foreseeable future? · plain
“Gut microbiota status, such as alpha diversity, can be used as a biomarker to predict the response to anti-PD-1 immunotherapy in NSCLC patients.”
Quote in the paperSubstantial claim - Also stated in: § How might it impact on clinical practice in the foreseeable future? · plain
- Study design and conductown data
No bacteria contamination during the GF cultivation condition was confirmed by time-course 16S rRNA sequencing.
“No bacteria contamination during the GF cultivation condition was confirmed by time-course 16S rRNA sequencing (online supplemental file 7A–B).”
Quote in the paperSubstantial claim - Interpretationown data
GPs could influence tryptophan metabolism through gut microbes.
“suggesting that GPs could influence tryptophan metabolism through gut microbes.”
Quote in the paperSubstantial claim - Interpretationown data
GPs sensitise the outcome of αPD-1 mAb therapy in recipient mice receiving faecal microbiota from NR donors by reshaping the gut microbiome from NRs towards that of Rs.
“This finding suggests that GPs sensitise the outcome of αPD-1 mAb therapy in recipient mice receiving faecal microbiota from NR donors by reshaping the gut microbiome from NRs towards that of Rs.”
Quote in the paperSubstantial claim - Premisecitation
P. distasonis enhances immune checkpoint inhibitor-mediated anticancer immunity by inducing production of IFNγ+CD8+ T cells.
“P. distasonis has been shown to enhance immune checkpoint inhibitor-mediated anticancer immunity by inducing the production of IFNγ+CD8+ T cells.53 54”
Quote in the paperNot a substantial claim0 of 2 sources checked - Interpretationreasoning
GPs may improve the response to PD-1 inhibitor via decreasing IDO activity.
“Collectively, GPs may improve the response to PD-1 inhibitor via decreasing IDO activity.”
Quote in the paperSubstantial claim - Interpretationown data
GPs combined with αPD-1 mAb improve the response rate by reinstating the gut microbiota.
“GPs combined with αPD-1 mAb improve the response rate by reinstating the gut microbiota.”
Quote in the paperSubstantial claim
- May combine two claims. 23
- Classified as probably not a substantial claim. 11
May combine two claims.
Findingown dataFewer Treg cells were observed in the combination group, and this was associated with improved treatment efficacy.
“We also observed fewer Treg cells in the combination group, which was associated with improved treatment efficacy (figure 6G).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIncreased proportions of RORγt+ Treg cells and reduced proportions of Th17 cells were found in the colon lamina propria in the combination treatment group.
“As expected, increased proportions of RORγt+ Treg cells and reduced proportions of Th17 cells were found in the combination treatment group (figure 3K, L).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataIn mice treated with GPs plus αPD-1 mAb, the ratio of CD8+/CD4+ T cells and the production of IFN-γ, TNF-α, and GZMB in CD8+ T cells were increased in both blood and tumours.
“Flow cytometry analysis and IHC profiles suggested that the ratio of CD8+/CD4+ T cells and the production of IFN-γ, TNF-α and GZMB in CD8+ T cells were increased both in the blood and tumours (figure 6C–F, H–M).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataAfter combination treatment, the microbial composition changed and the abundance of Muribaculum was significantly increased compared with αPD-1 mAb alone.
“After combination treatment, the microbial composition was changed and the abundance of Muribaculum was significantly increased compared with αPD-1 mAb alone group (figure 3A, B).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataGPs markedly increased production of L-tryptophan and reduced production of L-kynurenine and the Kyn/Trp ratio in human faecal samples under both aerobic and anaerobic fermentation conditions.
“Interestingly, we found that GPs markedly increased the production of L-tryptophan and reduced the production of L-kynurenine, as well as the kynurenine/tryptophan ratio both under aerobic and anaerobic fermentation conditions (online supplemental table 1)”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe potentiated antitumour effect of GPs plus αPD-1 mAb was also observed in humanised PD-1 knock-in (HuPD-1) mice with LLC cells and in B16-F10 tumour-bearing mice.
“We also observed this potentiated antitumour effect in HuPD-1 mice with LLC cells (figure 1E, F) and B16-F10 tumour-bearing mice (online supplemental figure 1B, C).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataL-kynurenine and the kynurenine/tryptophan (Kyn/Trp) ratio were markedly decreased in the combination treatment group compared with the αPD-1 mAb alone group, while L-tryptophan was not.
“We observed tryptophan metabolism contributes most among these metabolites with a marked decrease of L-kynurenine and the ratio of Kyn/Trp (expressed as IDO activity) but not L-tryptophan in the combination treatment group compared with the αPD-1 mAb alone group (online supplemental file 4A–D, Figure 4H–J).”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
PremisecitationInhibitors of programmed death 1 (PD-1) and its ligand PD-L1 are effective therapies for metastatic NSCLC lacking sensitising EGFR or ALK mutations.
“Inhibitors of programmed death 1 (PD-1) and its ligand PD-L1 are effective therapies for metastatic NSCLC lacking sensitising EGFR or ALK mutations.2–6”
Quote in the paperSubstantial claim0 of 5 sources checked- cites [2] source
Not checked in the free run.
- cites [3] source
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- cites [4] source
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- cites [5] Vokes, 2018, Nivolumab versus docetaxel in previously treated advanced non-small-cell lung cancer (CheckMate 017 and CheckMate 057): 3-year update and outcomes in patients with liver metastases, Ann Oncol source
Not checked in the free run.
- cites [6] source
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May combine two claims.
Interpretationown dataGPs increased the antitumour response to αPD-1 mAb by increasing valeric acid and decreasing L-kynurenine and the Kyn/Trp ratio, which contributed to suppression of regulatory T cells and induction of Teff cells after combination treatment.
“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.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataCombination treatment may take effect by activating CD8+ T cells and suppressing the function of Tregs.
“These results indicated that combination treatment may take effect by activating CD8+ T cells and suppressing the function of Tregs.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationIn human subjects, the family Bacteroidaceae and the genus Bacteroides were the predominant Bacteroidetes members.
“Whereas, in human subjects, the family Bacteroidaceae and the genus Bacteroides were the predominant Bacteroidetes members.38”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [38] source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
InterpretationcitationValerate may serve as an HDAC inhibitor to delay tumour progression and upregulate immune response.
“We reason valerate may serve as HDAC inhibitor to delay tumour progression and upregulate immune response.41 42”
Quote in the paperNot a substantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationLong-term administration of ginseng extracts modulates the rat gut microbiota by increasing the abundance of Bifidobacterium, Allobaculum, Lactobacillus, Clostridium and Parasutterella.
“The long-term administration of ginseng extracts has been shown to modulate the rat gut microbiota by increasing the abundance of Bifidobacterium, Allobaculum, Lactobacillus, Clostridium and Parasutterella.16”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [16] Sun, 2018, [Effect of long-term intake of ginseng extracts on gut microbiota in rats], Zhongguo Zhong Yao Za Zhi
Not checked in the free run.
Classified as probably not a substantial claim.
PremisecitationIDO activity has been proposed to be a possible mechanism of resistance to anti-PD-1 treatment.
“IDO activity has been proposed to be a possible mechanism of resistance to anti-PD-1 treatment, and several combination therapies have been launched into clinical trials.43–45”
Quote in the paperSubstantial claim0 of 3 sources checkedMay combine two claims.
Interpretationown dataThe antitumour effect was attributable to enhanced CD8+ functional T cells and downregulation of Treg cells by altering the gut microbiome.
“Our present study overscores the antitumour effect was attributable to the enhanced CD8+ functional T cells and the downregulation of Treg cells by altering the gut microbiome.”
Quote in the paperSubstantial claim- Rests on an assumption: Microbial metabolites intermediate the communication between microbiota and immune cells.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationGPs reinstate gut homeostasis, particularly by enhancing the growth of Lactobacillus spp and Bacteroides spp., which may reverse overfatigue and acute cold stress phenotypes by enhancing host immune function.
“Zhou et al demonstrated that GPs reinstate gut homeostasis, particularly by enhancing the growth of two major metabolic bacteria, Lactobacillus spp and Bacteroides spp., which may reverse overfatigue and acute cold stress phenotypes by enhancing host immune function.36”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [36] Zhou, 2016, Gut microbiota-involved mechanisms in enhancing systemic exposure of ginsenosides by coexisting polysaccharides in ginseng decoction, Sci Rep source
Not checked in the free run.
May combine two claims.
PremisecitationS24-7 was the predominant Bacteroidetes member in mice and was reported to be associated with better response to immunotherapy.
“S24-7 was the predominant Bacteroidetes member in mice and was reported to be associated with better response to immunotherapy.37”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [37] Uribe-Herranz, 2018, Gut microbiota modulates adoptive cell therapy via CD8α dendritic cells and IL-12, JCI Insight source
Not checked in the free run.
May combine two claims.
PremisecitationGPs improve intestinal metabolism and modulate the gut microbiota, particularly enhancing the growth of Lactobacillus spp. and Bacteroides spp.
“Moreover, GPs improve intestinal metabolism and modulate the gut microbiota and particularly enhance the growth of Lactobacillus spp. and Bacteroides spp., two major species of bacteria that metabolise ginsenosides.19 20”
Quote in the paperSubstantial claim0 of 1 sources checked- cites 19 20
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationBacteroides spp. have a protective effect on gastrointestinal toxicity during CTLA-4 mAb treatment.
“Bacteroides spp. have a protective effect on gastrointestinal toxicity during CTLA-4 mAb treatment.13”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [13] source
Not checked in the free run.
May combine two claims.
InterpretationreasoningSCFAs and kynurenine trafficked into the circulation and enhanced immune function, thereby suppressing tumour growth and prolonging survival.
“The metabolites SFCAs and kynurenine trafficked into circulating system and enhanced the immune function thus suppressing tumour growth and prolonging survival.”
Quote in the paperSubstantial claim- Rests on an assumption: Microbial metabolites intermediate the communication between microbiota and immune cells.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationGinsenosides could decrease the concentration of kynurenine and the Kyn/Trp ratio in mouse plasma.
“A previous study revealed that ginsenosides could decrease the concentration of kynurenine and the Kyn/Trp ratio in mouse plasma,50”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [50] source
Not checked in the free run.
May combine two claims.
InterpretationreasoningThe reduced Kyn/Trp ratio is consistent with the enhanced αPD-1 mAb response and increased survival time.
“This result is consistent with the enhanced αPD-1 mAb response and increased survival time.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationIn Chinese advanced NSCLC patients receiving nivolumab, Alistipes putredinis, Bifidobacterium longum and Prevotella copri were enriched in responding patients, whereas Ruminococcus_unclassified was enriched in non-responding patients.
“Jin et al enrolled 37 Chinese advanced NSCLC patients receiving nivolumab and patients using second-generation sequencing, found an enrichment of Alistipes putredinis, Bifidobacterium longum and Prevotella copri in responding patients, whereas Ruminococcus_unclassified was enriched in non-responding patients.51”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [51] Jin, 2019, The diversity of gut microbiome is associated with favorable responses to Anti-Programmed death 1 immunotherapy in Chinese patients with NSCLC, J Thorac Oncol source
Not checked in the free run.
May combine two claims.
Interpretationown dataGPs potentiate the antitumour effect of αPD-1 mAb by enhancing CD8+ T cell function and reducing the suppressive effect of Tregs, which might be addressed by reshaping the gut microbiota and tryptophan metabolism.
“In summary, we revealed that GPs potentiate the antitumour effect of αPD-1 mAb by enhancing CD8+ T cell function and reducing the suppressive effect of Tregs, which might be addressed by reshaping the gut microbiota and tryptophan metabolism.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationIDO-1 is a promising immune checkpoint associated with attenuation of Treg cell activation.
“IDO-1 is still a promising immune checkpoint which is associated with the attenuation of Treg cell activation.47”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [47] Melaiu, 2020, News on immune checkpoint inhibitors as immunotherapy strategies in adult and pediatric solid tumors, Semin Cancer Biol
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationB. vulgatus and P. distasonis are two species of commensal healthy bacteria.
“B. vulgatus and P. distasonis are two species of commensal healthy bacteria.52”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [52] Gu, 2020, Mutated CEACAMs disrupt transforming growth factor beta signaling and alter the intestinal microbiome to promote colorectal carcinogenesis, Gastroenterology source
Not checked in the free run.
May combine two claims.
Interpretationown dataCombination therapy significantly suppressed tumour growth by enhancing CD8+ T cell function, increasing production of IFN-γ, TNF-α, and granzyme B, and decreasing Treg cells.
“Meanwhile, combination therapy significantly suppressed tumour growth by enhancing the function of CD8+ T cells, increasing the production of IFN-γ, TNF-α, and granzyme B and decreasing Treg cells.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataCombination therapy reinstated gut microbiota, helping to revert gut microbiota from non-responders to responders, thus potentiating the response to αPD-1 mAb.
“Combination therapy reinstated gut microbiota which helps to revert gut microbiota from non-responders to responders, thus potentiating the response to αPD-1 mAb.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationA higher Kyn/Trp ratio leads to induction of Treg production, suppression of Teff cell production, and poor survival.
“The higher ratio of Kyn/Trp leads to the induction of Treg production and the suppression of Teff cell production, as well as poor survival.48 49”
Quote in the paperSubstantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationThe genus Bacteroides enhances the antitumour effect and alleviates gastrointestinal toxicity in melanoma patients treated with CTLA-4 blockade.
“The genus Bacteroides enhance the antitumour effect and alleviate the gastrointestinal toxicity in melanoma patients treated with CTLA-4 blockade.13”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [13] source
Not checked in the free run.
The paper relies on this without support.
The therapeutic potential of ginseng polysaccharides has not been well explored in cancer immunotherapy.
“Nevertheless, the therapeutic potential of GPs has not been well explored in cancer immunotherapy.”
The paper relies on this without support.
Ginseng polysaccharides have immunomodulatory functions, such as activation of macrophages, T cells and natural killer cells.
“Among these components, ginseng polysaccharides (GPs) have been demonstrated to be responsible for the immunomodulatory functions, such as the activation of macrophages, T cells and natural killer cells.”
The paper relies on this without support.
Microbial metabolites intermediate the communication between microbiota and immune cells.
“Microbial metabolites intermediate the communication between microbiota and immune cells.”
The paper relies on this without support.
SCFAs result from polysaccharide degradation by microbes.
“SCFAs result from polysaccharide degradation by microbes.”
The paper relies on this without support.
Previous studies show different groups got different microbes associated with response to PD-1 inhibitor, mainly concentrated on western people.
“Previous studies show different groups got different microbes associated with the response to PD-1 inhibitor, which mainly concentrated on western people.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Manipulating gut microbiota composition could improve the response to α-PD-1/PD-L1.
“Besides, manipulating gut microbiota composition could improve the response to α-PD-1/PD-L1 [311, 314–316].”
From Combination strategies with PD-1/PD-L1 blockade: current advances and future directions (2022) · cites this paper as [316]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Statistical methods say all data use SEM, but a figure reports SD
MinorThe statistical-analysis section says all data are expressed as mean±SEM, while the Figure 2 caption says its data are expressed as mean±SD.
“All data are expressed as the mean±SEM”
“Data represent the mean±SD and were analysed by one-way ANOVA.”
Kynurenine is described as both reduced to improve immunity and enhancing immunity
MinorThe abstract attributes the improved antitumour response partly to decreased L-kynurenine. The Figure 7 caption instead says kynurenine enhanced immune function and suppressed tumour growth.
“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”
“The metabolites SFCAs and kynurenine trafficked into circulating system and enhanced the immune function thus suppressing tumour growth and prolonging survival.”
Cites
Bray, F., Ferlay, J., Soerjomataram, I., Siegel, R. L., Torre, L. A., & Jemal, A. (2018) · CA: A Cancer Journal for Clinicians · doi:10.3322/caac.21492 · Cited by 84,109 · see citing works
Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer
Borghaei, H., Paz-Ares, L., Horn, L., Spigel, D. R., Steins, M., Ready, N. E., Chow, L. Q., Vokes, E. E., Felip, E., Holgado, E., et al. (2015) · New England Journal of Medicine · doi:10.1056/nejmoa1507643 · Cited by 9,335 · see citing works
Pembrolizumab plus chemotherapy in metastatic non–small-cell lung cancer
Gandhi, L., Rodríguez-Abreu, D., Gadgeel, S., Esteban, E., Felip, E., De Angelis, F., Domine, M., Clingan, P., Hochmair, M. J., Powell, S. F., et al. (2018) · New England Journal of Medicine · doi:10.1056/nejmoa1801005 · Cited by 6,607 · see citing works
Pembrolizumab for the Treatment of Non–Small-Cell Lung Cancer
Garon, E. B., Rizvi, N. A., Hui, R., Leighl, N., Balmanoukian, A. S., Eder, J. P., Patnaik, A., Aggarwal, C., Gubens, M., Horn, L., et al. (2015) · New England Journal of Medicine · doi:10.1056/nejmoa1501824 · Cited by 6,198 · see citing works
Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors
Routy, B., Le Chatelier, E., Derosa, L., Duong, C. P. M., Alou, M. T., Daillère, R., Fluckiger, A., Messaoudene, M., Rauber, C., Roberti, M. P., et al. (2018) · Science · doi:10.1126/science.aan3706 · Cited by 5,671 · see citing works
Elements of cancer immunity and the cancer–immune set point
Chen, D. S., & Mellman, I. (2017) · Nature · doi:10.1038/nature21349 · Cited by 5,352 · see citing works
Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients
Gopalakrishnan, V., Spencer, C. N., Nezi, L., Reuben, A., Andrews, M. C., Karpinets, T. V., Prieto, P. A., Vicente, D., Hoffman, K., Wei, S. C., et al. (2018) · Science · doi:10.1126/science.aan4236 · Cited by 4,812 · see citing works
Self-citationRittmeyer, A., Barlési, F., Waterkamp, D., Park, K., Ciardiello, F., von Pawel, J., Gadgeel, S. M., Hida, T., Kowalski, D. M., Cobo, M., et al. (2016) · The Lancet · doi:10.1016/s0140-6736(16)32517-x · Cited by 4,684 · see citing works
Commensal <i>Bifidobacterium</i> promotes antitumor immunity and facilitates anti–PD-L1 efficacy
Sivan, A., Corrales, L., Hubert, N., Williams, J. B., Aquino-Michaels, K., Earley, Z. M., Benyamin, F. W., Man Lei, Y., Jabri, B., Alegre, M.-L., et al. (2015) · Science · doi:10.1126/science.aac4255 · Cited by 3,888 · see citing works
Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota
Vétizou, M., Pitt, J. M., Daillère, R., Lepage, P., Waldschmitt, N., Flament, C., Rusakiewicz, S., Routy, B., Roberti, M. P., Duong, C. P. M., et al. (2015) · Science · doi:10.1126/science.aad1329 · Cited by 3,488 · see citing works
Gut microbiota, metabolites and host immunity
Rooks, M. G., & Garrett, W. S. (2016) · Nature reviews. Immunology · doi:10.1038/nri.2016.42 · Cited by 3,409 · see citing works
Fehrenbacher, L., Spira, A., Ballinger, M., Kowanetz, M., Vansteenkiste, J., Mazieres, J., Park, K., Smith, D., Artal-Cortes, A., Lewanski, C., et al. (2016) · The Lancet · doi:10.1016/s0140-6736(16)00587-0 · Cited by 2,756 · see citing works
Pelaseyed, T., Bergström, J. H., Gustafsson, J. K., Ermund, A., Birchenough, G. M. H., Schütte, A., van der Post, S., Svensson, F., Rodríguez‐Piñeiro, A. M., Nyström, E. E. L., et al. (2014) · Immunological Reviews · doi:10.1111/imr.12182 · Cited by 1,363 · see citing works
Loss of IFN-γ pathway genes in tumor cells as a mechanism of resistance to anti-CTLA-4 therapy
Gao, J., Shi, L. Z., Zhao, H., Chen, J., Xiong, L., He, Q., Chen, T., Roszik, J., Bernatchez, C., Woodman, S. E., et al. (2016) · Cell · doi:10.1016/j.cell.2016.08.069 · Cited by 1,300 · see citing works
T cell metabolism drives immunity
Buck, M. D., O’Sullivan, D., & Pearce, E. L. (2015) · The Journal of Experimental Medicine · doi:10.1084/jem.20151159 · Cited by 1,190 · see citing works
Champiat, S., Dercle, L., Ammari, S., Massard, C., Hollebecque, A., Postel-Vinay, S. C., Chaput, N., Eggermont, A. M. M., Marabelle, A., Soria, J., et al. (2016) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-16-1741 · Cited by 1,188 · see citing works
A defined commensal consortium elicits CD8 T cells and anti-cancer immunity
Tanoue, T., Morita, S., Plichta, D. R., Skelly, A. N., Suda, W., Sugiura, Y., Narushima, S., Vlamakis, H., Motoo, I., Sugita, K., et al. (2019) · Nature · doi:10.1038/s41586-019-0878-z · Cited by 1,145 · see citing works
PD-1 + regulatory T cells amplified by PD-1 blockade promote hyperprogression of cancer
Kamada, T., Togashi, Y., Tay, C., Ha, D., Sasaki, A., Nakamura, Y., Sato, E., Fukuoka, S., Tada, Y., Tanaka, A., et al. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1822001116 · Cited by 1,006 · see citing works
Lagkouvardos, I., Lesker, T. R., Hitch, T. C. A., Gálvez, E. J. C., Smit, N., Neuhaus, K., Wang, J., Baines, J. F., Abt, B., Stecher, B., et al. (2019) · Microbiome · doi:10.1186/s40168-019-0637-2 · Cited by 780 · see citing works
Increase of regulatory T cells in the peripheral blood of cancer patients.
Wolf, A. M., Wolf, D. G. F., Steurer, M., Gastl, G., Gunsilius, E., & Grubeck-Loebenstein, B. (2003) · PubMed · Cited by 655 · see citing works
Jin, Y., Dong, H., Xia, L., Yang, Y., Zhu, Y., Shen, Y., Zheng, H., Yao, C., Wang, Y., & Lu, S. (2019) · Journal of Thoracic Oncology · doi:10.1016/j.jtho.2019.04.007 · Cited by 573 · see citing works
Self-citationHeinhuis, K. M., Ros, W., Kok, M., Steeghs, N., Beijnen, J. H., & Schellens, J. H. M. (2019) · Annals of Oncology · doi:10.1093/annonc/mdy551 · Cited by 556 · see citing works
Britton, G. J., Contijoch, E. J., Mogno, I., Vennaro, O. H., Llewellyn, S. R., Ng, R., Li, Z., Mortha, A., Merad, M., Das, A., et al. (2019) · Immunity · doi:10.1016/j.immuni.2018.12.015 · Cited by 549 · see citing works
Novel patterns of response under immunotherapy
Borcoman, É., Kanjanapan, Y., Champiat, S., Kato, S., Servois, V., Kurzrock, R., Goel, S., Bedard, P. L., & Tourneau, C. L. (2019) · Annals of Oncology · doi:10.1093/annonc/mdz003 · Cited by 519 · see citing works
Luu, M., Pautz, S., Kohl, V., Singh, R., Romero, R., Lucas, S., Hofmann, J., Raifer, H., Vachharajani, N., Carrascosa, L. C., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-08711-2 · Cited by 508 · see citing works
IDO Activates Regulatory T Cells and Blocks Their Conversion into Th17-Like T Cells
Baban, B., Chandler, P., Sharma, M. D., Pihkala, J. P. S., Koni, P. A., Munn, D. H., & Mellor, A. L. (2009) · The Journal of Immunology · doi:10.4049/jimmunol.0900986 · Cited by 494 · see citing works
Vokes, E. E., Ready, N., Felip, E., Horn, L., Burgio, M. A., Antonia, S. J., Frontera, O. A., Gettinger, S. N., Holgado, E., Spigel, D. R., et al. (2018) · Annals of Oncology · doi:10.1093/annonc/mdy041 · Cited by 464 · see citing works
Labadie, B. W., Bao, R., & Luke, J. J. (2019) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-18-2882 · Cited by 413 · see citing works
Hyperprogressive disease during PD-1/PD-L1 blockade in patients with non-small-cell lung cancer
Kim, C. G., Kim, K. H., Pyo, K., Xin, C.-F., Hong, M. H., Ahn, B., Kim, Y., Choi, S. J., Yoon, H. I., Lee, J. G., et al. (2019) · Annals of Oncology · doi:10.1093/annonc/mdz123 · Cited by 282 · see citing works
Jung, K. H., LoRusso, P. M., Burris, H. A., Gordon, M. S., Bang, Y., Hellmann, M. D., Cervantes, A. M. R., de Olza, M. O., Marabelle, A., Hodi, F. S., et al. (2019) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-18-2740 · Cited by 277 · see citing works
Nagpal, R., Wang, S., Woods, L. C. S., Seshie, O., Chung, S. T., Shively, C. A., Register, T. C., Craft, S., McClain, D. A., & Yadav, H. (2018) · Frontiers in Microbiology · doi:10.3389/fmicb.2018.02897 · Cited by 270 · see citing works
Jia, L., Zhao, Y., & Liang, X. (2009) · Current Medicinal Chemistry · doi:10.2174/092986709788803204 · Cited by 269 · see citing works
Myristoleic acid produced by enterococci reduces obesity through brown adipose tissue activation
Quan, L., Zhang, C., Dong, M., Jiang, J., Xu, H., Yan, C., Liu, X., Zhou, H., Zhang, H., Chen, L., et al. (2019) · Gut · doi:10.1136/gutjnl-2019-319114 · Cited by 254 · see citing works
Metabolomic adaptations and correlates of survival to immune checkpoint blockade
Li, H., Bullock, K., Gurjao, C., Braun, D., Shukla, S. A., Bossé, D., Lalani, A.-K. A., Gopal, S., Jin, C., Horak, C., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-12361-9 · Cited by 218 · see citing works
Zhou, S.-S., Xu, J., Zhu, H., Wu, J., Xu, J., Yan, R., Li, X., Liu, H.-H., Duan, S.-M., Wang, Z., et al. (2016) · Scientific Reports · doi:10.1038/srep22474 · Cited by 185 · see citing works
Self-citationGut microbiota modulates adoptive cell therapy via CD8α dendritic cells and IL-12
Uribe-Herranz, M., Bittinger, K., Rafail, S., Guedan, S., Pierini, S., Tanes, C., Ganetsky, A., Morgan, M. A., Gill, S., Tanyi, J. L., et al. (2018) · JCI Insight · doi:10.1172/jci.insight.94952 · Cited by 175 · see citing works
Sun, Y. (2011) · Carbohydrate Polymers · doi:10.1016/j.carbpol.2011.03.033 · Cited by 166 · see citing works
Schewe, M., Franken, P., Sacchetti, A., Schmitt, M., Joosten, R., Böttcher, R., van Royen, M. E., Jeammet, L., Payré, C., Scott, P. M., et al. (2016) · Cell stem cell · doi:10.1016/j.stem.2016.05.023 · Cited by 122 · see citing works
Nishitsuji, K., Xiao, J., Nagatomo, R., Umemoto, H., Morimoto, Y., Akatsu, H., Inoue, K., & Tsuneyama, K. (2017) · Scientific Reports · doi:10.1038/s41598-017-16189-5 · Cited by 119 · see citing works
An, K., Hao, H., Zheng, X., Liang, Y. L., Xie, Y., Xie, T., Dai, C., Zhao, Q., Wu, X., Xie, L. Y., et al. (2011) · Journal of Neuroinflammation · doi:10.1186/1742-2094-8-100 · Cited by 105 · see citing works
Self-citationQu, C. F., Yuan, Z., Yu, X., Huang, Y., Yang, G., Chen, J., Lai, X., Su, Z., Zeng, H., Xie, Y., et al. (2017) · Pharmacological Research · doi:10.1016/j.phrs.2017.04.017 · Cited by 93 · see citing works
Self-citationHDAC6 selective inhibition of melanoma patient T-cells augments anti-tumor characteristics
Laino, A. S., Betts, B. C., Veerapathran, A., Dolgalev, I., Sarnaik, A. A., Quayle, S. N., Jones, S. S., Weber, J. S., & Woods, D. M. (2019) · Journal for ImmunoTherapy of Cancer · doi:10.1186/s40425-019-0517-0 · Cited by 82 · see citing works
News on immune checkpoint inhibitors as immunotherapy strategies in adult and pediatric solid tumors
Melaiu, O., Lucarini, V., Giovannoni, R., Fruci, D., & Gemignani, F. (2020) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2020.07.001 · Cited by 75 · see citing works
Gu, S., Zaidi, S., Hassan, M. I., Mohammad, T., Malta, T. M., Noushmehr, H., Nguyen, B., Crandall, K. A., Srivastav, J., Obias, V., et al. (2020) · Gastroenterology · doi:10.1053/j.gastro.2019.09.023 · Cited by 63 · see citing works
Isolation and Flow Cytometric Characterization of Murine Small Intestinal Lymphocytes
Couter, C. J., & Surana, N. K. (2016) · Journal of Visualized Experiments · doi:10.3791/54114 · Cited by 56 · see citing works
Ikpa, P. T., Sleddens, H. F. B. M., Steinbrecher, K. A., Peppelenbosch, M. P., de Jonge, H. R., Smits, R., & Bijvelds, M. J. C. (2016) · Histochemistry and Cell Biology · doi:10.1007/s00418-016-1453-4 · Cited by 56 · see citing works
Graf, J., Ledala, N., Caimano, M. J., Jackson, E., Gratalo, D., Fasulo, D., Driscoll, M. D., Coleman, S., & Matson, A. P. (2021) · mBio · doi:10.1128/mbio.03656-20 · Cited by 49 · see citing works
Luo, J., Han, L., Liu, L., Gao, L., Xue, B., Wang, Y., Ou, S., Miller, M. J., & Peng, X. (2018) · Food & Function · doi:10.1039/c8fo00035b · Cited by 37 · see citing works
Self-citationWang, W., Huang, L., Jin, J., et al. (2019) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-19-1202 · Cited by 33 · see citing works
Self-citationTranscriptome analysis of the distal small intestine of Cftr null mice
Ikpa, P. T., Meijsen, K. F., Nieuwenhuijze, N. D. A., Dulla, K., de Jonge, H. R., & Bijvelds, M. J. C. (2019) · Genomics · doi:10.1016/j.ygeno.2019.06.028 · Cited by 23 · see citing works
[Effect of long-term intake of ginseng extracts on gut microbiota in rats].
Sun, Y., Zhang, X., Wang, X., et al. (2018) · PubMed · doi:10.19540/j.cnki.cjcmm.20180604.001 · Cited by 20 · see citing works
Echoes of a failure: what lessons can we learn?
Sondak, V. K., & Khushalani, N. I. (2019) · The Lancet Oncology · doi:10.1016/s1470-2045(19)30312-2 · Cited by 17 · see citing works
Yang, S.-H., Seo, S.-H., Kim, S.-W., et al. (2006) · Archives of Pharmacal Research · doi:10.1007/bf02974072 · Cited by 17 · see citing works
Nomura, M., Nagatomo, R., Inoue, K., Doi, K., Shimizu, J., Baba, K., Saito, T., Matsumoto, S., & Muto, M. (2019) · Annals of Oncology · doi:10.1093/annonc/mdz253.074 · Cited by 10 · cited 1× · see citing works
“40 In this study, we also observed that all the SCFAs including propionate, butyrate, isobutyrate, valerate, isovalerate and hexanoate, increased after treatment with α PD-1 mAb.”
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Combination strategies with PD-1/PD-L1 blockade: current advances and future directions
Yi, M., Zheng, X., Niu, M., Zhu, S., Ge, H., & Wu, K. (2022) · Molecular Cancer · doi:10.1186/s12943-021-01489-2 · Cited by 1,445 · see citing works
Bolte, L. A., Lee, K. A., Björk, J. R., Leeming, E. R., Campmans-Kuijpers, M. J. E., de Haan, J. J., Vila, A. V., Maltez-Thomas, A., Segata, N., Board, R., et al. (2023) · JAMA Oncology · doi:10.1001/jamaoncol.2022.7753 · Cited by 106 · see citing works
Jamal, R., Messaoudene, M., de Figuieredo, M., & Routy, B. (2023) · Seminars in Immunology · doi:10.1016/j.smim.2023.101754 · Cited by 31 · see citing works
- Authors
- Huang, J., Liu, D., Wang, Y., Liu, L., Li, J., Yuan, J., Jiang, Z., Jiang, Z., Hsiao, W. W., Liu, H., Khan, I., Xie, Y., Wu, J., Xie, Y., Zhang, Y., Fu, Y., Liao, J., Wang, W., Lai, H., Shi, A., Cai, J., Luo, L., Li, R., Yao, X., Fan, X., Wu, Q., Liu, Z., Yan, P., Lu, J., Yang, M., Wang, L., Cao, Y., Wei, H., & Leung, E. L.-H.
- Affiliations
- Macau University of Science and Technology (MO)
- Chinese Academy of Sciences (CN)
- The First Affiliated Hospital, Sun Yat-sen University (CN)
- Capital Institute of Pediatrics (CN)
- Dr 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
- Guangdong Medical College (CN)
- Guangzhou University of Chinese Medicine (CN)
- Kiang Wu Hospital (CN)
- Corresponding author
- Leung, Elaine Lai-Han
- ORCID
- Venue
- Gut
- Publisher
- BMJ
- Published
- 2021-05-18
- Volume
- 71
- Issue
- 4
- Pages
- 734-745
- ISSN
- 0017-5749 (ISSN-L)
- 1468-3288
- PMC
- PMC8921579
- OpenAlex
- W3162194652
- Semantic Scholar
- bc74a41a381c6ad12ff2fe72f73b8a62972745b8
- Cited by
- 539
- References
- 54
- Citations by year
- 2026: 96 · 2025: 145 · 2024: 135 · 2023: 89 · 2022: 64 · 2021: 9
- FWCI
- 27.41
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Gut (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (001/2020/ALC)
- Fundo para o Desenvolvimento das Ciências e da Tecnologia (001/2020/ALC, 0096/2018/A3)
- Army Medical University
- Macau University of Science and Technology (001/2020/ALC)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ginseng Biological Effects and Applications
- Keywords
- ginseng polysaccharides, gut microbiota, kynurenine/tryptophan ratio, PD-1/PD-L1 blockade, immune checkpoint blockade, non-small cell lung cancer, immunotherapy response biomarkers, valeric acid, L-kynurenine, regulatory T cells, Parabacteroides distasonis, Bacteroides vulgatus, fecal microbiota transplantation, combination therapy
- MeSH terms
- Gastrointestinal Microbiome, Animals, Antibodies, Monoclonal, Carcinoma, Non-Small-Cell Lung, Panax, Humans, Immunologic Factors, Immunotherapy, Kynurenine, Ligands, Lung Neoplasms, Polysaccharides, Tryptophan, Cell Death, Apoptosis, Mice, B7-H1 Antigen
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