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Cited by 115Gut microbiota and healthCancer Immunotherapy and BiomarkersCancer Research and Treatments

Gut Microbiome as a Potential Factor for Modulating Resistance to Cancer Immunotherapy

Open access
Shui, Lin, Yang, Xi, Li, Jian, Yi, Cheng, Sun, Qin, Zhu, Hong·2020·Frontiers in Immunology
DOI 10.3389/fimmu.2019.02989PMC PMC6978681
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Abstract

Gut microbiota refers to the diverse community of more than 100 trillion microorganisms residing in our intestines. It is now known that any shift in the composition of gut microbiota from that present during the healthy state in an individual is associated with predisposition to multiple pathological conditions, such as diabetes, autoimmunity, and even cancer. Currently, therapies targeting programmed cell death protein 1/programmed cell death 1 ligand 1 or cytotoxic T-lymphocyte antigen-4 are the focus of cancer immunotherapy and are widely applied in clinical treatment of various tumors. Owing to relatively low overall response rate, however, it has been an ongoing research endeavor to identify the mechanisms or factors for improving the therapeutic efficacy of these immunotherapies. Other than causing mutations that affect gene expression, some gut bacteria may also activate or repress the host's response to immune checkpoint inhibitors. In this review, we have described recent advancements made in understanding the regulatory relationship between gut microbiome and cancer immunotherapy. We have also summarized the potential molecular mechanisms behind this interaction, which can serve as a basis for utilizing different kinds of gut bacteria as promising tools for reversing immunotherapy resistance in cancer.

AI snapshot

Written from the paper’s full text.

TL;DR

This review summarizes evidence that gut microbiome composition modulates cancer immunotherapy response, especially immune checkpoint inhibitors, through mechanisms such as cytokine production, dendritic cell activation, Treg modulation, and chemokine induction. It argues that manipulating microbiota via FMT, probiotics, antibiotics, or metabolites may help reverse immunotherapy resistance, but species-level mechanisms and clinical biomarkers remain unresolved.

Key findings

  • In metastatic melanoma, among 42 patients before PD-1 blockade, the clinical response rate was 38% (16 responders/26 non-responders); 10 bacterial species differed, 8 enriched in responders including Bifidobacterium. FMT from responders into tumor-bearing germ-free mice led to inferior tumor growth in 2 of 3 mice, and PD-1 inhibitor worked in responder-colonized but not non-responder-colonized mice.
  • Gopalakrishnan et al. evaluated 112 melanoma patients on PD-1 blockade; higher gut bacterial diversity was associated with prolonged PFS, with Clostridiales/Ruminococcaceae/Faecalibacterium enriched in responders and Bacteroidales/E. coli in non-responders. Routy et al. found antibiotics shortened PFS and OS, while Akkermansia muciniphila and Enterococcus hirae were enriched in patients with best clinical response (PFS > 3 months).
  • Anti-CTLA-4 efficacy depended on microbiota: it was effective in SPF but not germ-free mice, antibiotics abolished the effect, and Bacteroides/Burkholderia recolonization restored response. In 26 ipilimumab-treated melanoma patients, Bacteroides were associated with poor clinical benefit and higher Faecalibacterium with longer survival.
  • Proposed mechanisms include increased IFN-γ and IL-12, dendritic cell activation/maturation, decreased peripherally derived Tregs, and chemokine-mediated T-cell recruitment; short-chain fatty acids and bacterial molecules such as polysaccharide A are implicated.

Methods

  • Narrative review; no primary experiments or new patient data. It synthesizes recent preclinical mouse models and human clinical studies on gut microbiome and cancer immunotherapy.
  • Main analysis is qualitative synthesis of cited studies across ICIs (PD-1/PD-L1, CTLA-4), CpG-oligonucleotide immunotherapy, and adoptive cell therapy, plus proposed mechanisms and tables of bacteria and manipulation strategies.

Limitations

  • Stated: incomplete understanding of which specific microbial species drive better immune response; no consensus across similar cohorts and treatments; the tumor microenvironment is cancer-type-specific; cross-species FMT relevance is uncertain; and the Wang et al. ICI-colitis FMT case had a small sample.
  • Evident: as a narrative review, it lacks systematic search and quality appraisal and does not quantitatively pool results; findings rely on heterogeneous preclinical and clinical studies, with contradictory results noted, such as microbial depletion reducing versus promoting tumor growth.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.3389/fimmu.2019.02989

Cites

Statistics

Nothing to recompute.

Claims the paper makes

0 of 118 cited sources checked · 0 supported · 0 flagged

  • Interpretationnone given

    Some gut bacteria may activate or repress the host's response to immune checkpoint inhibitors.

    “Other than causing mutations that affect gene expression, some gut bacteria may also activate or repress the host's response to immune checkpoint inhibitors.”
    Quote in the paperNot a substantial claim
  • Premisereasoning

    Gut microbiota can affect the function of intestinal mucosal immunity.

    “In general, gut microbiota can affect the function of intestinal mucosal immunity.”
    Quote in the paperSubstantial claim
  • Interpretationreasoning

    Adhesion of intestinal bacteria to intestinal epithelial cells may regulate the generation and differentiation of Th17 cells by sending a certain signal.

    “All of the above-mentioned evidence support that the adhesion of intestinal bacteria to intestinal epithelial cells may regulate the generation and differentiation of Th17 cells by sending a certain signal, but the exact mechanism remains to be further explored.”
    Quote in the paperNot a substantial claim
  • Premisereasoning

    Microbiota restrict the function of gut γδ IEL.

    “Nonetheless, microbiota do restrict the function of gut ɤδ IEL.”
    Quote in the paperNot a substantial claim
  • Premisenone given

    Immune activation of one local site may result in altered immune microenvironment at another distal site.

    “In this system, immune activation of one local site may result in altered immune microenvironment at another distal site.”
    Quote in the paperSubstantial claim
  • Classified as probably not a substantial claim. 11
  • May combine two claims. 55

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Earlier, multiple studies showed a correlation between gut microbiome and cancer therapy, such as the chemotherapy-elicited anticancer immune response of cyclophosphamide.

    “Earlier, multiple studies showed a correlation between gut microbiome and cancer therapy, such as the chemotherapy-elicited anticancer immune response of cyclophosphamide (42, 43).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [42] Daillère, 2016, Enterococcus hirae and Barnesiella intestinihominis facilitate cyclophosphamide-induced therapeutic immunomodulatory effects, Immunity. source

      Not checked in the free run.

    • cites [43] Viaud, 2013, The intestinal microbiota modulates the anticancer immune effects of cyclophosphamide, Science. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Dysbiosis is associated with several physiological as well as pathological changes in the host.

    “Dysbiosis is associated with several physiological as well as pathological changes in the host.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Bifidobacterium strengthened antitumor immunity and raised the efficacy of PD-L1 blocking therapy.

    “In 2015, Sivan et al. (54) proposed that Bifidobacterium, a specific taxon of microbial commensals, strengthened antitumor immunity and raised the efficacy of PD-L1 blocking therapy.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Sivan et al. (54) Sivan, 2015, Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy, Science. source

      Not checked in the free run.

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    Interpretationcitation

    Microbiota can alter not only the antitumor immunity but also the response to PD-L1 inhibitors.

    “suggesting that microbiota can alter not only the antitumor immunity but also the response to PD-L1 inhibitors.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [54] Sivan, 2015, Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy, Science. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Ten bacterial species differed between responders and non-responders, and 8 of those were more abundant in responders, including Bifidobacterium.

    “The authors selected 10 bacterial species that were different between R and NR, 8 of those were found to be more abundant in R (including Bifidobacterium, also observed in preclinical studies).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [55] Matson, 2018, The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients, Science. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Detection of invasive bacteria by γδ IELs balances intestinal microbiota through crosstalk with adjacent epithelial cells, thereby acting as a vital component of the immune system.

    “In short, these studies illustrate that detection of invasive bacteria by ɤδ IELs balances intestinal microbiota through crosstalk with adjacent epithelial cells, thereby acting as a vital component of the immune system.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    Prophylactic transfer of JAX fecal suspensions to TAC-recipient mice impeded tumor growth and enhanced infiltration of tumor-specific CD8+ T cells.

    “Compared to saline or TAC fecal material, prophylactic transfer of JAX fecal suspensions to TAC-recipient mice impeded tumor growth and enhanced infiltration of tumor-specific CD8+ T cells.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [54] Sivan, 2015, Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy, Science. source

      Not checked in the free run.

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    Premisecitation

    Only less than half the patients respond to ICIs initially, and another subgroup becomes resistant during continued treatment.

    “However, only less than half the patients respond to ICIs initially, and another subgroup becomes resistant during continued treatment, suggesting the presence of natural-acquired or therapy-induced resistance (25).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [25] Kelderman, 2014, Acquired and intrinsic resistance in cancer immunotherapy, Mol Oncol. source

      Not checked in the free run.

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    Premisecitation

    PD-1 inhibitor exerted its antitumor activity in mice colonized with R bacteria but was ineffective in NR bacteria colonized mice.

    “As expected, PD-1 inhibitor exerted its antitumor activity in mice colonized with R bacteria but was ineffective in NR bacteria colonized mice, thus confirming in vivo the influence of gut microbiome on human immunity.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [55] Matson, 2018, The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients, Science. source

      Not checked in the free run.

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    Premisecitation

    Clostridiales/Ruminococcaceae/Faecalibacterium were abundant in responders and Bacteroidales/Escherichia coli in non-responders.

    “They showed an abundance of Clostridiales/Ruminococcaceae/Faecalibacterium in R and Bacteroidales/Escherichia coli in NR (Figure 2) (57).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [57] Gopalakrishnan, 2018, Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients, Science. source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    Intestinal flora is not only related to intestinal immune diseases but also has an important impact beyond the gut.

    “Intestinal flora is not only related to intestinal immune diseases but also has an important impact beyond the gut.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Antibiotic treatment compromised the antitumor effect, with progression-free survival and overall survival being significantly shorter compared to the control group.

    “Their results showed that the antitumor effect was compromised in ATB treatment group, with progression-free survival (PFS) and overall survival (OS) being significantly shorter compared to that of the control group”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [56] Routy, 2017, Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors, Science. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    JAX mice had 257 more taxa than TAC mice, and Bifidobacterium operational taxonomic unit_681370 increased over 400 times in JAX-fed TAC mice.

    “JAX mice were shown to have 257 more taxa than TAC mice, and it was the Bifidobacterium operational taxonomic unit_681370 that increased over 400 times in JAX-fed TAC mice (54).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [54] Sivan, 2015, Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy, Science. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Management of gut microbiome elicits modification of TME and turns on a switch for the development of resistance to immune therapy, which enables tumor cells to escape immune surveillance.

    “In other words, management of gut microbiome elicits modification of TME and turns on a switch for the development of resistance to immune therapy, which enables tumor cells to escape immune surveillance.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [67] Vetizou, 2015, Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota, Science. source

      Not checked in the free run.

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    Premisecitation

    In mouse models of cervical and lung cancer with E6/E7 human papillomavirus protein expression, ACT was more effective in HAR mice and almost completely abrogated tumor growth.

    “ACT was more effective in HAR mice receiving ACT and almost completely abrogated tumor growth.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [80] 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.

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    Premisecitation

    Responding patients harbored higher diversity and stable composition of innate gut microbiome during treatment and also had significantly prolonged PFS.

    “According to their results, responding patients harbored higher diversity and stable composition of innate gut microbiome during treatment and also had significantly prolonged PFS.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [58] 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.

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    Premisecitation

    Patients with longer survival had a smaller proportion of baseline Tregs and a lower frequency of effector T cells compared to those with shorter PFS.

    “who also had a smaller proportion of baseline Tregs and a lower frequency of effector T cells compared to those with shorter PFS.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [68] Chaput, 2017, Baseline gut microbiota predicts clinical response and colitis in metastatic melanoma patients treated with ipilimumab, Ann Oncol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Transplantation of fecal microbiota from responders delayed tumor growth, increased the accumulation of CXCR3CD4+ T cells and CD8+ T cells, and upregulated PD-L1 expression in the TME, thereby counteracting the impaired anticancer ability against PD-L1 blockade.

    “Compared to NR-FMT mice, transplantation of fecal microbiota from R patients delayed tumor growth, increased the accumulation of CXCR3CD4+ T cells and CD8+ T cells, and upregulated PD-L1 expression in the TME, thereby counteracting the impaired anticancer ability against PD-L1 blockade.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [56] Routy, 2017, Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors, Science. source

      Not checked in the free run.

    • cites [57] Gopalakrishnan, 2018, Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients, Science. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Patients with more non-responder microorganisms often had a shortened PFS and a higher level of Tregs with a blunted cytokine response.

    “In contrast, patients with more NR microorganisms often had a shortened PFS and a higher level of Tregs with a blunted cytokine response.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [57] Gopalakrishnan, 2018, Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients, Science. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    TCR-engineered T cells or CAR-engineered T cells increase the efficacy of the antitumor immune response.

    “TCR-engineered T cells or CAR-engineered T cells increase the efficacy of the antitumor immune response (79).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [79] Chiara, 2015, Adoptive T-cell therapy for cancer: the era of engineered T cells, Eur J Immunol. source

      Not checked in the free run.

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    Premisecitation

    ACT efficacy increased when bacterial composition was altered following depletion of Gram-positive taxa by antibiotics, but was unchanged after depletion of Gram-negative bacteria.

    “ACT efficacy increased when the bacterial composition was altered following depletion of Gram-positive taxa by antibiotics, but it was unchanged after depletion of Gram-negative bacteria.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [80] 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.

    Premisecitation

    Dietary supplements with Bacteroides fragilis induced Th1 immune responses in the tumor-draining lymph nodes, prompted the maturation of DCs in the TME, and facilitated the restoration of the clinical response to CTLA-4 blockade.

    “In fact, dietary supplements with Bacteroides fragilis induced Th1 immune responses in the tumor-draining lymph nodes prompted the maturation of DCs in the TME and facilitated the restoration of the clinical response to CTLA-4 blockade.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [67] Vetizou, 2015, Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota, Science. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Bacteroides were present in majority of the patients with poor clinical benefit, but a higher proportion of Faecalibacterium existed in patients with longer survival.

    “Bacteroides were present in majority of the patients with poor clinical benefit, but a higher proportion of Faecalibacterium existed in patients with longer survival (68)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [68] Chaput, 2017, Baseline gut microbiota predicts clinical response and colitis in metastatic melanoma patients treated with ipilimumab, Ann Oncol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    FMT from non-responder patients to GF mice led to the development of resistance for PD-1 blockade, with colonization of A. muciniphila and E. hirae being able to reverse the compromised efficacy.

    “Furthermore, FMT from NR patients to GF mice led to the development of resistance for PD-1 blockade, with colonization of A. muciniphila and E. hirae being able to reverse the compromised efficacy (56).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [56] Routy, 2017, Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors, Science. source

      Not checked in the free run.

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    Premisecitation

    A combination of antibiotics or imipenem alone destroyed the function of CTLA-4 inhibitors against the tumor.

    “A combination of ATBs (ampicillin, colistin, and streptomycin) or imipenem alone destroyed the function of CTLA-4 inhibitors against the tumor.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [67] Vetizou, 2015, Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota, Science. source

      Not checked in the free run.

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    Premisecitation

    Alistipes putredinis, Bifidobacterium longum, and Prevotella copri were enriched in responders, whereas Ruminococcus_unclassified was found mainly in non-responding patients.

    “In detail, Alistipes putredinis, Bifidobacterium longum, and Prevotella copri were enriched in responders, whereas Ruminococcus_unclassified was found mainly in non-responding patients.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [58] 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.

    Premisecitation

    Suppressing IL-10R promotes CD4+ T cell proliferation and increases hepatitis C virus-specific interferon-gamma production.

    “The results showed that suppressing IL-10R could promote CD4+ T cell proliferation and increase hepatitis C virus-specific interferon-gamma (IFN-ɤ) production (75).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [75] Rigopoulou, 2005, Blocking of interleukin-10 receptor–a novel approach to stimulate T-helper cell type 1 responses to hepatitis C virus, Clin Immunol. source

      Not checked in the free run.

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    Premisecitation

    The therapeutic effect of CpG and anti-IL10R results from enhanced tumor-infiltrating DCs and macrophage infiltrate switching from M2 to M1, producing increased IL-12 and TNF.

    “The therapeutic effect resulting from enhanced tumor-infiltrating DCs and macrophage infiltrate switching from M2 to M1 consequently produce increased IL-12 and tumor necrosis factor (TNF) (76).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [76] Vicari, 2002, Reversal of tumor-induced dendritic cell paralysis by CpG immunostimulatory oligonucleotide and anti-interleukin 10 receptor antibody, J Exp Med. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Patients with more Faecalibacterium had a significantly prolonged PFS with higher level of effector T cells and a stabilized cytokine response to PD-1 blockade.

    “Patients with more Faecalibacterium also had a significantly prolonged PFS with higher level of effector T cells and a stabilized cytokine response to PD-1 blockade.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [57] Gopalakrishnan, 2018, Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients, Science. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Bacterial ablation led to a reduction in myeloid-derived suppressor cells, increased M1 macrophage differentiation, enhanced CD4+ T-cell differentiation and CD8+ T-cell activation.

    “Bacterial ablation led to a reduction in myeloid-derived suppressor cells, increased M1 macrophage differentiation, enhanced CD4+ T-cell differentiation and CD8+ T-cell activation.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [59] Pushalkar, 2018, The pancreatic cancer microbiome promotes oncogenesis by induction of innate and adaptive immune suppression, Cancer Discov. source

      Not checked in the free run.

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    Premisecitation

    SCFAs produced by commensal bacteria during starch fermentation strongly modulate gene expression in human monocyte-derived DCs, reducing secretion of multiple proinflammatory chemokines and inhibiting expression of LPS-induced cytokines with enhanced activity against inflammation.

    “Short-chain fatty acids (SCFAs), such as acetate, butyrate, and propionate, produced by commensal bacteria during starch fermentation, strongly modulate gene expression in human monocyte-derived DCs, thus reducing the secretion of multiple proinflammatory chemokines and inhibiting the expression of LPS-induced cytokines with enhanced activity against inflammation (110).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [110] Nastasi, 2015, The effect of short-chain fatty acids on human monocyte-derived dendritic cells, Sci Rep. source

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    Premisecitation

    Expression of PD-1 on DCs significantly affects release of IL-2 and IFN-gamma and reduces proliferation of antigen-specific CD8+ T cells.

    “A recent study showed that the expression of PD-1 on DCs significantly affects the release of IL-2 and IFN-ɤ and reduces the proliferation of antigen-specific CD8+ T cells (108).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [108] Lim, 2016, PD-1 expression on dendritic cells suppresses CD8+ T cell function and antitumor immunity, Oncoimmunology. source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Main environmental factors including diet, lifestyle, evolutionary history, immune system, age, and antibiotics influence the composition of the gut microbiota.

    “However, the main environmental factors, including diet lifestyle, evolutionary history, immune system, age, and antibiotics still influence the composition of the gut microbiota (86).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [86] Boehme, 2019, Mid-life microbiota crises: middle age is associated with pervasive neuroimmune alterations that are reversed by targeting the gut microbiome, Mol Psychiatry. source

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    Premisecitation

    Gut microbiota depletion in a mice model significantly increases IFN-gamma-producing T cells and decreases IL-17A and IL-10-producing T cells, thereby reducing tumor growth.

    “Sethi et al. (87) found that gut microbiota depletion in a mice model significantly increases IFN-ɤ-producing T cells and correspondingly decreases the IL 17A and IL 10-producing T cells, thereby reducing tumor growth.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [87] Sethi, 2018, Gut microbiota promotes tumor growth in mice by modulating immune response, Gastroenterology. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Bacteria can differentially affect the T-cell immune response and potentially remold the cold or suppressive TME into a hot or responsive one.

    “Some of the above-mentioned studies showed that bacteria can differentially affect the T-cell immune response and potentially remold the “cold” or suppressive TME into a “hot” or responsive one.”
    Quote in the paperSubstantial claim

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    Premisecitation

    IL-12 blocking antibody application and IL-12-KO mice successfully offset the heightened response of ACT, verifying that the effects of the gut microbiome on adoptive transfer therapy depend on IL-12.

    “Recent studies (80) have demonstrated that IL-12 blocking antibody application and IL-12-KO mice successfully offset the heightened response of ACT, therefore verifying that the effects of the gut microbiome on adoptive transfer therapy depend on IL-12.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [80] Uribe-Herranz, 2018, Gut microbiota modulates adoptive cell therapy via CD8α dendritic cells and IL-12, JCI Insight. source

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  • May combine two claims.

    Interpretationcitation

    Increase in IL-12 levels might enhance the efficacy of immunotherapy by increasing production of IFN-gamma to stimulate development and enhance cytotoxicity of activated NK cells and T cells and accelerate differentiation of CD4+ Th0 cells toward Th1 phenotype, thus improving antibody-dependent cellular cytotoxicity.

    “Therefore, increase in IL-12 levels might enhance the efficacy of immunotherapy by increasing the production of IFN-ɤ to stimulate the development and enhance the cytotoxicity of activated NK cells (100) and T cells and to accelerate the differentiation of CD4+ Th0 cells toward the Th1 phenotype, thus improving antibody-dependent cellular cytotoxicity (101).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [100] Robin, 2002, IL-12 enhances the natural killer cell cytokine response to Ab-coated tumor cells, J Clin Investig. source

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    • cites [101] Luedke, 2012, Cetuximab therapy in head and neck cancer: Immune modulation with interleukin-12 and other natural killer cell–activating cytokines, Surgery. source

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    Premisecitation

    In a cervical cancer mice model treated with adoptive T cell therapy, concurrent use of vancomycin can reduce tumor progression, mainly due to the opposite effect of vancomycin-sensitive Gram-negative bacteria.

    “Uribe-Herranz et al. (80) have shown that, in a cervical cancer mice model treated with adoptive T cell therapy, the concurrent use of vancomycin can reduce tumor progression, mainly due to the opposite effect of the vancomycin-sensitive Gram-negative bacteria.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [80] Uribe-Herranz, 2018, Gut microbiota modulates adoptive cell therapy via CD8α dendritic cells and IL-12, JCI Insight. source

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  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Routy et al. proposed that the restoration may be IL-12 dependent and increase recruitment of CD4+ T lymphocytes into tumor beds.

    “Routy et al. (56) proposed that the restoration may be IL-12 dependent and increase the recruitment of CD4+ T lymphocytes into tumor beds.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [56] Routy, 2017, Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors, Science. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Wang et al. reported the first case of ICI-associated colitis successfully treated with FMT, with reconstitution of the gut microbiota and a relative increase in the proportion of Treg cells within the colonic mucosa.

    “Wang et al. (84) reported the first case of ICI-associated colitis successfully treated with FMT, with reconstitution of the gut microbiota and a relative increase in the proportion of Treg cells within the colonic mucosa.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [84] Wang, 2018, Fecal microbiota transplantation for refractory immune checkpoint inhibitor-associated colitis, Nat Med. source

      Not checked in the free run.

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    Premisecitation

    Tanoue et al. isolated IFN-gamma+ CD8 T-cell-inducing bacteria strains from healthy human microbiota and indicated they work as a consortium in which four non-Bacteroidales species are effector elements and seven Bacteroidales play a supporting role.

    “Tanoue et al. (88) have isolated successfully IFNɤ+ CD8 T-cell-inducing bacteria strains from healthy human microbiota and indicated that they work as a consortium in which the four non-Bacteroidales species are effector elements and the seven Bacteroidales play a supporting role.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [88] Tanoue, 2019, A defined commensal consortium elicits CD8 T cells and anti-cancer immunity, Nature. source

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    Premisecitation

    IFN-gamma upregulates MHC expression on tumor cells and M1 macrophages and facilitates recognition and elimination of transformed cells.

    “IFN-ɤ, an important cytokine involved in antitumor immunity, could upregulate MHC expression on tumor cells and M1 macrophages and facilitate the recognition and elimination of transformed cells (91, 92).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [91] Timothy, 2012, Cancer immunoediting by the innate immune system in the absence of adaptive immunity, J Exp Med. source

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    • cites [92] Kursunel, 2016, The untold story of IFN-γ in cancer biology, Cytokine Growth Factor Rev. source

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  • May combine two claims.

    Interpretationcitation

    Bifidobacterium mitigates gut immunopathology without compromising the effects of immunotherapy.

    “In addition, decreased secretion of inflammatory cytokines such as KC, IL-6, and CFS3 as observed with the same growth kinetics of the tumor, indicating that Bifidobacterium mitigates gut immunopathology without compromising on the effects of immunotherapy.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [83] Wang, 2018, Bifidobacterium can mitigate intestinal immunopathology in the context of CTLA-4 blockade, Proc Natl Acad Sci USA. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Propionates affect DC and macrophage biology in the bone marrow and regulate Th2 cell responses in the airway of the mouse model.

    “Propionates affect DC and macrophage biology in the bone marrow and regulate Th2 cell responses in the airway of the mouse model (111).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [111] Aurélien, 2014, Gut microbiota metabolism of dietary fiber influences allergic airway disease and hematopoiesis, Nat Med. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CTLA-4 downregulates upon differentiation into immature DCs and is considerably upregulated on mature DCs.

    “CTLA-4 has been reported to downregulate upon differentiation into immature DCs and considerably upregulated on mature DCs (109).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [109] Laurent, 2010, CTLA-4 is expressed by human monocyte-derived dendritic cells and regulates their functions, Hum Immunol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Gut bacteria that significantly prolong PFS show a preserved cytokine response to PD-1-target treatment, whereas antibiotics decrease the level of cytokines in TME.

    “The gut bacteria that significantly prolong PFS show a preserved cytokine response to PD-1-target treatment, whereas antibiotics have been demonstrated to decrease the level of cytokines in TME (67).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [67] Vetizou, 2015, Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota, Science. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Orally feeding B. fragilis induced Th1 immune response in tumor-draining lymph nodes and catalyzed maturation of DCs in the TME, facilitating restoration of clinical response to CTLA-4 blockade.

    “orally feeding B. fragilis induced Th1 immune response in the tumor-draining lymph nodes and catalyzed the maturation of DCs in the TME, facilitating the restoration of the clinical response to CTLA-4 blockade (67).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [67] Vetizou, 2015, Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota, Science. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Increased population of CD8α+ DCs in the spleens of ATB-treated mice with ACT results in enhanced ability to cross-present tumor antigens to CD8+ T cells and increased secretion of Th1 cytokines such as IL-12 and IFN-gamma.

    “An increased population of CD8α+ DCs in the spleens of ATB-treated mice with ACT results in enhanced ability to cross-present tumor antigens to CD8+ T cells and increased secretion of Th1 cytokines such as IL-12 and IFN-ɤ (80).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [80] 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.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Previous results have tried to utilize the gut microbiota as a potential biomarker for pancreatic cancer.

    “Previous results have tried to utilize the gut microbiota as a potential biomarker for pancreatic cancer (123).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [123] Farrell, 2012, Variations of oral microbiota are associated with pancreatic diseases including pancreatic cancer, Gut. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationcitation

    Beneficial bacteria and their metabolites promote differentiation and proliferation of Tregs, leading to elevated CTLA-4 levels and improved sensitivity to CTLA-4 blockade by abrogating immunosuppression in the TME.

    “It is presumed that beneficial bacteria and their metabolites promote the differentiation and proliferation of Tregs, leading to elevated CTLA-4 levels and improved sensitivity to CTLA-4 blockade by abrogating immunosuppression in TME (68).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [68] Chaput, 2017, Baseline gut microbiota predicts clinical response and colitis in metastatic melanoma patients treated with ipilimumab, Ann Oncol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Patients with non-beneficial bacteria presented higher levels of Tregs in their systemic circulation, whereas patients with long-term benefit presented a low level of Tregs at baseline.

    “Patients with non-beneficial bacteria presented higher levels of Tregs in their systemic circulation, whereas patients with long-term benefit presented a low level of Tregs at the baseline (68).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [68] Chaput, 2017, Baseline gut microbiota predicts clinical response and colitis in metastatic melanoma patients treated with ipilimumab, Ann Oncol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In i.c. xenograft models, CCL5 was 70-fold higher, CCL20 19-fold higher, and CXCL10 12-fold higher than in i.p. xenografts, suggesting that exposure to gut flora resulted in a strong induction of chemokine expression.

    “The i.c. models showed a striking 70-fold higher level of CCL5, 19-fold higher level of CCL20, and 12-fold higher level of CXCL10 levels than those in i.p. xenografts, suggesting that exposure to gut flora resulted in a strong induction of chemokine expression.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [117] Cremonesi, 2018, Gut microbiota modulate T cell trafficking into human colorectal cancer, Gut. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a PDAC microbiome study, endogenous bacterial dysbiosis triggered immune suppression, but Treg differentiation did not differ in PDAC-bearing and WT mice.

    “In their study on PDAC microbiome, Pushalkar et al. (59) found that, although endogenous bacterial dysbiosis triggered immune suppression, Treg differentiation did not differ in PDAC-bearing and WT mice.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [59] Pushalkar, 2018, The pancreatic cancer microbiome promotes oncogenesis by induction of innate and adaptive immune suppression, Cancer Discov. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Polysaccharide A produced by B. fragilis promotes development of an inducible population of CD4+Foxp3+ Tregs, which inhibits regulation of the immune system.

    “Polysaccharide A, a microbial molecule produced by B. fragilis, promotes the development of an inducible population of CD4+Foxp3+ Tregs, a subset of Tregs, which inhibits the regulation of the immune system (113).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [113] Round, 2010, Inducible Foxp3+ regulatory T-cell development by a commensal bacterium of the intestinal microbiota, Proc Natl Acad Sci USA. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The number of Foxp3+ T cells isolated from the spleen was not different between PBS- and Bifidobacterium-treated mice, but genes targeted to certain metabolic pathways of Tregs were expressed differentially.

    “Similar results were observed in another study (117), where the number of Foxp3+ T cells isolated from the spleen was not different between PBS- and Bifidobacterium-treated mice, but genes targeted to certain metabolic pathways of Tregs, such as cellular macromolecules and organic substances, were expressed differentially.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [117] Cremonesi, 2018, Gut microbiota modulate T cell trafficking into human colorectal cancer, Gut. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Some gut bacteria act as suppressors of inhibitory signal pathways, facilitate antigen presentation, and improve specific antitumor immunity.

    “Some gut bacteria act as suppressors of inhibitory signal pathways, facilitate antigen presentation, and improve specific antitumor immunity (118).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [118] Yi, 2018, Gut microbiome modulates efficacy of immune checkpoint inhibitors, J Hematol Oncol. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A ratio of over 1.5 of beneficial to non-beneficial operational taxonomic units indicated clinical benefit.

    “For instance, some researchers calculated the proportion of “beneficial” and “non-beneficial” operational taxonomic units and their ratio for every patient and reached a limit conclusion—a ratio of over 1.5 indicated clinical benefit (55).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [55] Matson, 2018, The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients, Science. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Blautia obeum, Roseburia intestinalis, and some combination of antibiotics compromised the efficacy of immunotherapy.

    “However, Blautia obeum, Roseburia intestinalis, and some combination of antibiotics (56, 59, 77) compromised the efficacy of immunotherapy (Table 1).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [56] Routy, 2017, Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors, Science. source

      Not checked in the free run.

    • cites [59] Pushalkar, 2018, The pancreatic cancer microbiome promotes oncogenesis by induction of innate and adaptive immune suppression, Cancer Discov. source

      Not checked in the free run.

    • cites [77] Cristiana, 2005, Redirecting in vivo elicited tumor infiltrating macrophages and dendritic cells towards tumor rejection, Cancer Res. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    The main challenge is the incomplete understanding of the special microbial species involved in better immune response.

    “The main challenge encountered is the incomplete understanding of the special microbial species involved in better immune response.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    One reason for the difference in results is that the tumor microenvironment is unique for the type of cancer and is exclusively sensitive to the specific commensal microbiota.

    “One reason for the difference in results is that TME is unique for the type of cancer and is exclusively sensitive to the specific commensal microbiota.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Uniform results on the composition of the microbiota are lacking, suggesting that there may be other unidentified factors underlying this complicated process.

    “Uniform results on the composition of the microbiota are lacking, suggesting that there may be other unidentified factors underlying this complicated process.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premiseown data

    Alloprevotella, Treponema, and Desulfovibrio were abundant in CRC tumors infiltrated with CD3+ T cells, whereas overexpression of Prevotella, Bacteroides, and Fretibacterium was more frequent in CD3low tumors.

    “An analysis of gut microbiota constituents in CRC samples to elucidate the relationship with specific bacteria and T-cell infiltration showed that Alloprevotella, Treponema, and Desulfovibrio were abundant in tumors infiltrated with CD3+ T cells, whereas the overexpression of Prevotella, Bacteroides, and Fretibacterium was more frequent in CD3low tumors.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    It remains undetermined whether cross-species microbiota transplantation reflects conditions in humans.

    “In addition, many studies have used FMT in experimental animals, and whether the cross-species microbiota transplantation reflects conditions in humans remains to be determined.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Many studies have used fecal microbiota transplantation in experimental animals.

  • May combine two claims.

    Premisecitation

    Tregs isolated from GF mice and stimulated in vitro with propionate showed a significant increase in Foxp3 expression, suggesting that SCFAs could specifically induce Tregs.

    “In a recent study, Tregs isolated from GF mice and stimulated in vitro with propionate showed a significant increase in Foxp3 expression, which suggested that the SCFAs could specifically induce Tregs (82).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [82] Smith, 2013, The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis, Science. source

      Not checked in the free run.

64 of 64

  • The paper relies on this without support.

    Findings from mouse models and ex vivo studies about gut microbiome effects on immunotherapy are relevant to human cancer immunotherapy.

    “The above results showed that the gut microbiome plays an important role in the antitumor effectiveness of ACT.”

  • The paper relies on this without support.

    The composition and numbers of the microbial community fluctuate in a dynamic equilibrium under the influence of external factors.

    “As a microbial ecosystem, the composition and numbers of microbial community fluctuate in a dynamic equilibrium under the influence of external factors.”

  • The paper relies on this without support.

    The gut microbiome can be manipulated to improve immunotherapy outcomes in humans.

    “FMT could be used as a potential strategy to ameliorate the resistance to immunotherapy and enhance the therapeutic effect of those drugs.”

  • The paper relies on this without support.

    Most antibiotics are highly effective and broad spectrum.

    “Considering that most ATBs are highly effective and broad spectrum”

  • The paper relies on this without support.

    Many studies have used fecal microbiota transplantation in experimental animals.

    “In addition, many studies have used FMT in experimental animals”
5 of 5

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?

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.

  • Conflicting accounts of which bacterial depletion improves ACT

    Major

    The account of the ACT study says efficacy increased after depletion of Gram-positive bacteria and was unchanged after depletion of Gram-negative bacteria. A later account attributes reduced tumor progression with vancomycin to its effect on Gram-negative bacteria.

  • Ipilimumab is described as both inhibiting and restoring T-cell activation

    Minor

    The paper calls ipilimumab an inhibitory regulator of T-cell activation, but later says it blocks CTLA-4 to revive the antitumor response of T cells.

2 of 2

The citation lists haven’t been fetched yet

References 136 · Cited by 115

Authors
Shui, L., Yang, X., Li, J., Yi, C., Sun, Q., & Zhu, H.
Affiliations
  • Sichuan University (CN)
  • Southwest Medical University (CN)
Corresponding author
  • Sun, Qin
  • Zhu, Hong
ORCID
Venue
Frontiers in Immunology
Publisher
Frontiers Media SA
Published
2020-01-17
Volume
10
Pages
2989-2989
ISSN
1664-3224 (ISSN-L)
DOI
10.3389/fimmu.2019.02989
PMC
PMC6978681
OpenAlex
W2999666394
Semantic Scholar
194e81cb48ec844e7b66b5f7f86a9e0d1149b7db
Cited by
115
References
136
Citations by year
2026: 5 · 2025: 10 · 2024: 15 · 2023: 15 · 2022: 29 · 2021: 28 · 2020: 13
FWCI
2.03
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Immunology (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
Sichuan University
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biotechnology › Cancer Research and Treatments
Keywords
gut microbiota, cancer immunotherapy, immunotherapy resistance, immune checkpoint inhibitors, PD-1/PD-L1, CTLA-4, microbiota-immune interactions, molecular mechanisms, microbiota-based therapy
MeSH terms
Gastrointestinal Microbiome, Animals, Bacteria, Humans, Immunotherapy, Neoplasms

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Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-07.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-07.

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