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Cited by 89Gut microbiota and healthCancer Immunotherapy and BiomarkersCutaneous Melanoma Detection and Management

Melanoma and microbiota: Current understanding and future directions

Open access
Routy, Bertrand, Jackson, Tanisha, Mählmann, Laura, Baumgartner, Christina K., Blaser, Martin, Byrd, Allyson, Corvaia, Nathalie, Couts, Kasey +23 more·2024·Cancer Cell
DOI 10.1016/j.ccell.2023.12.003PMC PMC11096984
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Abstract

Over the last decade, the composition of the gut microbiota has been found to correlate with the outcomes of cancer patients treated with immunotherapy. Accumulating evidence points to the various mechanisms by which intestinal bacteria act on distal tumors and how to harness this complex ecosystem to circumvent primary resistance to immune checkpoint inhibitors. Here, we review the state of the microbiota field in the context of melanoma, the recent breakthroughs in defining microbial modes of action, and how to modulate the microbiota to enhance response to cancer immunotherapy. The host-microbe interaction may be deciphered by the use of "omics" technologies, and will guide patient stratification and the development of microbiota-centered interventions. Efforts needed to advance the field and current gaps of knowledge are also discussed.

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Crossref · 10.1016/j.ccell.2023.12.003

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Claims the paper makes

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  • Premisecitation

    In mouse models, certain gut commensals mediate the efficacy of anticancer therapies including chemotherapy, radiotherapy, adoptive T cell transfer, intratumoral CpG-oligonucleotides, and immune checkpoint inhibitors.

    “In mouse models, certain gut commensals mediate efficacy of anticancer therapies, including chemotherapy, radiotherapy, and immunotherapies such as adoptive T cell transfer, intratumoral CpG-oligonucleotides, and ICIs.”
    Quote in the paperSubstantial claim0 of 6 sources checked
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  • Premisecitation

    Across cancer indications and geographic sites, the taxonomic composition of gut and to some degree tumor microbiota correlates with ICI responses in melanoma and other cancers.

    “First, correlations have been drawn across cancer indications and geographical sites between the taxonomic composition of the gut (and to some degree tumor) microbiota, and ICI responses in patients with melanoma and other cancers.”
    Quote in the paperSubstantial claim0 of 9 sources checked
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  • Premisenone given

    The composition of gut microbiota correlates with immunotherapy outcomes in cancer patients.

    “Over the last decade, the composition of the gut microbiota has been found to correlate with the outcomes of cancer patients treated with immunotherapy.”
    Quote in the paperSubstantial claim
  • Premisecitation

    The microbiota influences the cancer-immune set point, the threshold beyond which an immune response can be elicited in an individual.

    “The microbiota influences the cancer-immune set point, which is the threshold beyond which an immune response can be elicited in a given individual.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [11] Chen, 2017, Elements of cancer immunity and the cancer-immune set point, Nature source

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  • Premisecitation

    Broad-spectrum antibiotics taken before immunotherapy markedly reduce the clinical benefit of ICIs, CAR-T cells, stem cell transplantation, and immunogenic chemotherapy in preclinical tumor models.

    “In addition, broad-spectrum antibiotics (mainly beta-lactams) taken prior to immunotherapy markedly reduce the clinical benefit of ICIs, chimeric antigen receptor (CAR)-T cells, stem cell transplantation in patients, and immunogenic chemotherapy in preclinical tumor models.”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [3] Viaud, 2013, The intestinal microbiota modulates the anticancer immune effects of cyclophosphamide, Science source

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    • cites [4] Iida, 2013, Commensal bacteria control cancer response to therapy by modulating the tumor microenvironment, Science source

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    • cites [8] Stein-Thoeringer, 2023, A non-antibiotic-disrupted gut microbiome is associated with clinical responses to CD19-CAR-T cell cancer immunotherapy, Nat. Med. source

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  • May combine two claims. 31
  • Classified as probably not a substantial claim. 5

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    Findingcitation

    The authors constructed a co-abundance network from baseline shotgun metagenomic stool samples that depicted relative abundance interrelationships correlated with patient survival and enabled calculation of an individual ICI response probability score.

    “In addition to GOMS, we constructed a co-abundance network depicting relative abundance interrelationships correlated with patient survival using shotgun metagenomic stool samples at baseline, enabling calculation of an individual ICI response probability score (Derosa, Abstract 259MO, presented at ESMO Asia Congress 2022).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Derosa, Abstract 259MO, presented at ESMO Asia Congress 2022

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

    Premisenone given

    Host microbiota plays an important role in immunotherapy response and resistance.

    “Host microbiota plays an important role in immunotherapy response and resistance.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    Sufficient dietary fiber intake is associated with improved progression-free survival on ICIs, while untargeted probiotic exposure is associated with worse outcomes, and preclinical melanoma models support microbiota as mediators.

    “Furthermore, sufficient dietary fiber intake was associated with improved progression-free survival (PFS) with ICIs, while untargeted probiotic exposure was associated with worse outcomes, and preclinical melanoma models supported microbiota as mediators between these exposures and ICI outcomes.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [13] Spencer, 2021, Dietary fiber and probiotics influence the gut microbiome and melanoma immunotherapy response, Science source

      Not checked in the free run.

    • cites [20] Lam, 2021, Microbiota triggers STING-type I IFN-dependent monocyte reprogramming of the tumor microenvironment, Cell source

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    Premisecitation

    Pioneering clinical studies in melanoma patients showed that fecal microbiota transplant could circumvent primary and secondary ICI resistance or improve ICI response rates.

    “Finally, pioneering clinical studies in patients with melanoma showed that fecal microbiota transplant (FMT) could circumvent primary and secondary ICI resistance,28,29 or ameliorate ICI response rates.30”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [28] Davar, 2021, Fecal microbiota transplant overcomes resistance to anti-PD-1 therapy in melanoma patients, Science source

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    • cites [29] Baruch, 2021, Fecal microbiota transplant promotes response in immunotherapy-refractory melanoma patients, Science source

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    • cites [30] Routy, 2023, Fecal microbiota transplantation plus anti-PD-1 immunotherapy in advanced melanoma: a phase I trial, Nat. Med. source

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  • May combine two claims.

    Premisecitation

    Habitual high-fiber diet consumption is associated with improved progression-free survival in ICI-treated melanoma patients, and in mice dietary fiber deprivation abrogates response to ICIs and decreases stool propionate.

    “Habitual consumption of a high-fiber diet has also been associated with improved PFS in ICI-treated patients with melanoma.13 In mice, dietary fiber deprivation was further shown to abrogate response to ICIs and decrease stool propionate.13”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [13] Spencer, 2021, Dietary fiber and probiotics influence the gut microbiome and melanoma immunotherapy response, Science source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    High serum levels of butyrate and propionate are associated with resistance to anti-CTLA-4 antibodies and radiotherapy and with increased Treg cell numbers in melanoma patients.

    “High serum levels of butyrate and propionate have been associated with resistance to anti-CTLA-4 antibodies and radiotherapy and increased Treg cell numbers in patients with melanoma.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [7] Uribe-Herranz, 2020, Gut microbiota modulate dendritic cell antigen presentation and radiotherapy-induced antitumor immune response, J. Clin. Invest. source

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    • cites [54] Coutzac, 2020, Systemic short chain fatty acids limit antitumor effect of CTLA-4 blockade in hosts with cancer, Nat. Commun. source

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    Premisecitation

    High levels of microbiota-derived arginine are associated with improved progression-free survival in patients receiving ICIs, and in murine tumor models boosting L-arginine enhances the antitumor effects of ICIs in a T cell-dependent manner.

    “High levels of microbiota-derived arginine are associated with improved PFS in patients receiving ICIs. In murine tumor models, boosting L-arginine levels enhances the antitumor effects of ICIs in a T cell-dependent manner.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [45] Canale, 2021, Metabolic modulation of tumours with engineered bacteria for immunotherapy, Nature source

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    • cites [46] Peyraud, 2022, Circulating L-arginine predicts the survival of cancer patients treated with immune checkpoint inhibitors, Ann. Oncol. source

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    Premisecitation

    These pro-inflammatory species are often associated with poor prognosis and lack of responses to cancer immunotherapy.

    “These species are often associated with poor prognosis and lack of responses to cancer immunotherapy.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [15] Derosa, 2022, Intestinal Akkermansia muciniphila predicts clinical response to PD-1 blockade in patients with advanced non-small-cell lung cancer, Nat. Med. source

      Not checked in the free run.

    • cites [19] Lee, 2022, Cross-cohort gut microbiome associations with immune checkpoint inhibitor response in advanced melanoma, Nat. Med. source

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    Premisecitation

    Lactobacillus reuteri-derived indole-3-aldehyde improved ICI efficacy in mice, and melanoma patients responding to ICIs had higher serum indole-3-aldehyde levels than nonresponders.

    “L. reuteri-derived I3A improved ICI efficacy in mice, and melanoma patients responding to ICIs harbored higher serum I3A levels compared with nonresponders.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [49] Bender, 2023, Dietary tryptophan metabolite released by intratumoral Lactobacillus reuteri facilitates immune checkpoint inhibitor treatment, Cell source

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    Premisecitation

    Unrestrained inflammation contributes to oncogenesis and tumor progression, in part due to impaired immunosurveillance.

    “This phenomenon also applies to cancer control, as unrestrained inflammation contributes to (often age-related) oncogenesis as well as tumor progression, in part due to impaired immunosurveillance.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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    Premisecitation

    In mice, dysbiosis upregulates PD-L2 on dendritic cells and increases RGMb on CD8+ T cells, explaining resistance to PD-L1 blockade.

    “In mice, dysbiosis causes the upregulation of PD-L2 on DCs and increased expression of the PD-L2 receptor repulsive guidance molecule b (RGMb) on CD8+ T cells, hence explaining the resistance of cancers to PD-L1 blockade.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [42] Park, 2023, Targeting PD-L2-RGMb overcomes microbiome-related immunotherapy resistance, Nature source

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    Premisecitation

    After cyclophosphamide exposure, Enterococcus hirae translocation activates CD8+ T cells that recognize a latent bacteriophage encoded by the E. hirae genome and cross-react with tumor antigens, attenuating tumor progression.

    “For example, upon exposure to cyclophosphamide, Enterococcus hirae translocation leads to the activation of CD8+ T cells that recognize a latent bacteriophage encoded by the E. hirae genome and cross-react with tumor antigens, hence attenuating tumor progression.”
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    • cites [37] Fluckiger, 2020, Cross-reactivity between tumor MHC class I-restricted antigens and an enterococcal bacteriophage, Science source

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    Premisecitation

    Many bacteria linked to ICI response have known dietary associations, and dietary patterns such as plant-based versus western diet correlate with higher or lower relative abundances of these candidate taxa.

    “Many bacteria associated with ICI response have known dietary associations, such that specific dietary patterns (e.g., plant-based versus western diet) are associated with increased or decreased relative abundances of these candidate taxa.131–135”
    Quote in the paperSubstantial claim0 of 5 sources checked
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    • cites [135] Hiel, 2019, Effects of a diet based on inulin-rich vegetables on gut health and nutritional behavior in healthy humans, Am. J. Clin. Nutr. source

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    Premisecitation

    Quantitative PCR estimated that among seven cancer types approximately 0.68% (95% CI: 0.75, 1.46%) of tumor cellular content is bacterial, with melanoma-specific density estimates at about 33 bacteria/mm2 or 6.3×10^6 bacteria/cm3 on average.

    “Quantitative PCR has estimated that among seven cancer types, approximately 0.68% (95% CI: 0.75, 1.46%) of the tumor cellular content is bacterial, with melanoma-specific density estimates at ~33 bacteria/mm2 or ~6.3×106 bacteria/cm3 on average (using bootstrapped values).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [14] Nejman, 2020, The human tumor microbiome is composed of tumor type-specific intracellular bacteria, Science source

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    • cites [127] Sepich-Poore, 2022, Bioessays source

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    Premisecitation

    A growing body of evidence demonstrates the presence of intratumoral microbes, with studies suggesting intracellular, cancer type-specific, spatially heterogeneous, metabolically active, pro-metastatic, and immunoreactive communities of tumor-resident bacteria, fungi, and viruses, including in melanoma.

    “A growing body of evidence has demonstrated the presence of intratumoral microbes, with studies using either metagenomics or culturomics suggesting the presence of intracellular,14,38,102,103 cancer type-specific,14,104–106 spatially heterogeneous,14,103,107 metabolically active,14,38,49,108,109 pro-metastatic,102,103,110,111 and immunoreactive38,60,112–115 communities of tumor-resident bacteria,”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [14] Nejman, 2020, The human tumor microbiome is composed of tumor type-specific intracellular bacteria, Science source

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    • cites [38] Kalaora, 2021, Identification of bacteria-derived HLA-bound peptides in melanoma, Nature source

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    • cites [49] Bender, 2023, Dietary tryptophan metabolite released by intratumoral Lactobacillus reuteri facilitates immune checkpoint inhibitor treatment, Cell source

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    • cites [104] Poore, 2020, Microbiome analyses of blood and tissues suggest cancer diagnostic approach, Nature source

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    • cites [105] Narunsky-Haziza, 2022, Pan-cancer analyses reveal cancer-type-specific fungal ecologies and bacteriome interactions, Cell source

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    Premisecitation

    In humans, a fasting-mimicking diet reduces immunosuppressive myeloid cells and increases CD8+ T cells and NK cells.

    “In humans, a fasting-mimicking diet decreases immunosuppressive myeloid cells while increasing CD8+ T cells and NK cells.141”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [141] Vernieri, 2022, Fasting-Mimicking Diet Is Safe and Reshapes Metabolism and Antitumor Immunity in Patients with Cancer, Cancer Discov. source

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    Premisecitation

    In mice, ketogenic diet and caloric restriction have been verified to affect antitumor immunity and ICI response.

    “The effects of more specific/restrictive dietary interventions on antitumor immunity and ICI response, including ketogenic diet and caloric restriction, have also been verified in mice.139,140”
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    • cites [140] Ferrere, 2021, Ketogenic diet and ketone bodies enhance the anticancer effects of PD-1 blockade, JCI Insight source

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    Premisecitation

    L. reuteri converts dietary tryptophan into the AhR agonist indole-3-carbaldehyde, which is necessary and sufficient to enhance ICI efficacy in preclinical melanoma by activating AhR in CD8+ T cells and driving Tc1 immunity.

    “A recent preclinical study discovered that L. reuteri converts dietary tryptophan into the AhR agonist indole-3-carbaldehyde, which was necessary and sufficient to enhance ICI efficacy in preclinical melanoma via activation of AhR in CD8+ T cells and driving Tc1 immunity.49”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [49] Bender, 2023, Dietary tryptophan metabolite released by intratumoral Lactobacillus reuteri facilitates immune checkpoint inhibitor treatment, Cell source

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    Premisecitation

    The prebiotics inulin and mucin produce antitumor immune responses in melanoma-implanted mice but not in germ-free mice.

    “The prebiotics inulin and mucin produce antitumor immune responses in melanoma-implanted mice, but not in germ-free mice.146”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [146] Li, 2020, Prebiotic-Induced Anti-tumor Immunity Attenuates Tumor Growth, Cell Rep. source

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  • May combine two claims.

    Premisecitation

    In murine models, manipulating dietary fiber rapidly changes the microbiota and can enhance ICI effects in specific pathogen-free tumor-bearing mice.

    “causality is supported by preclinical studies in which dietary fiber manipulation in murine models rapidly shifts the microbiota and can potentiate the effect of ICIs in specific pathogen-free, tumor-bearing mice.13,20”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [13] Spencer, 2021, Dietary fiber and probiotics influence the gut microbiome and melanoma immunotherapy response, Science source

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    • cites [20] Lam, 2021, Microbiota triggers STING-type I IFN-dependent monocyte reprogramming of the tumor microenvironment, Cell source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a meta- and mega-analysis of stools from ICI-treated cancer patients, GOMS linked to ICI resistance comprised microorganisms affiliated with chronic inflammation, immunosuppression, and oral genera, and were shared across various pathological disorders.

    “A meta- and mega-analysis of stools obtained from patients with cancer treated with ICIs showed that GOMS associated with ICI resistance comprised microorganisms affiliated with chronic inflammation and immunosuppression and oral genera, and were shared across various pathological disorders.22,155”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [22] Thomas, 2023, Gut OncoMicrobiome Signatures (GOMS) as next-generation biomarkers for cancer immunotherapy, Nat. Rev. Clin. Oncol. source

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    • cites [155] Blanco-Míguez, 2023, Extending and improving metagenomic taxonomic profiling with uncharacterized species using MetaPhlAn 4, Nat. Biotechnol. source

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    Interpretationcitation

    The enhancement of ICI response by dietary fiber manipulation is absent in germ-free mice, which suggests that this effect requires microbiota.

    “Notably, this phenomenon is not seen in germ-free mice, suggesting that ICI response augmentation is microbiota dependent.13”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [13] Spencer, 2021, Dietary fiber and probiotics influence the gut microbiome and melanoma immunotherapy response, Science source

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  • Classified as probably not a substantial claim.

    Interpretationreasoning

    The finding that dietary tryptophan enhanced ICI efficacy without exogenous L. reuteri implies that tryptophan-catabolizing bacteria other than L. reuteri contribute to antitumor immunity.

    “This observation implies that other tryptophan-catabolizing bacteria besides L. reuteri contribute to antitumor immunity; this hypothesis should be further evaluated.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    GOMS are shared among individuals with seemingly unrelated disorders and are characterized by an imbalance between health-related and chronic inflammatory disease-related commensals.

    “this group of experts recently described Gut OncoMicrobiome Signatures (GOMS) across different cohorts of patients with cancer, histotypes, and geographical sites, and showed that GOMS are shared among individuals with seemingly unrelated disorders and characterized by an imbalance between health-related and chronic inflammatory disease-related commensals.22”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [22] Thomas, 2023, Gut OncoMicrobiome Signatures (GOMS) as next-generation biomarkers for cancer immunotherapy, Nat. Rev. Clin. Oncol. source

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    Premisecitation

    E. coli Nissle 1917 engineered to generate higher levels of L-arginine metabolically reprograms tumor microenvironments and enhances ICI antitumor activity.

    “E. coli Nissle 1917 has also been engineered to generate higher levels of L-arginine, which metabolically reprograms TMEs and enhances the efficacy of ICI antitumor activity.45”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [45] Canale, 2021, Metabolic modulation of tumours with engineered bacteria for immunotherapy, Nature source

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  • May combine two claims.

    Premisecitation

    Antibiotics may increase engraftment but have been associated with reduced ICI efficacy in patients not undergoing microbiota modulation.

    “Notably, antibiotics may increase engraftment but have been associated with reduced ICI efficacy in patients not undergoing microbiota modulation.167–169”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [167] Kim, 2019, The effect of antibiotics on the clinical outcomes of patients with solid cancers undergoing immune checkpoint inhibitor treatment: a retrospective study, BMC Cancer source

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    • cites [168] Zhang, 2023, Higher alpha diversity and Lactobacillus blooms are associated with better engraftment after Fecal Microbiota Transplant in Inflammatory Bowel Disease, medRxiv

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    • cites [169] Ji, 2017, Preparing the Gut with Antibiotics Enhances Gut Microbiota Reprogramming Efficiency by Promoting Xenomicrobiota Colonization, Front. Microbiol. source

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  • Classified as probably not a substantial claim.

    Interpretationcitation

    Nonresponse due to low tumor mutational burden, low pre-existing T cell-mediated immune responses, or a cold TME may overlap with nonresponse due to dysbiosis.

    “One might anticipate that nonresponse due to low tumor mutational burden, low pre-existing T cell-mediated immune responses, or a cold TME may overlap with nonresponse due to dysbiosis.171,172”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [171] Yang, 2021, Tumor-Infiltrating PD-1(hi)CD8(+)-T-Cell Signature as an Effective Biomarker for Immune Checkpoint Inhibitor Therapy Response Across Multiple Cancers, Front. Oncol.

      Not checked in the free run.

    • cites [172] Sha, 2020, Tumor Mutational Burden as a Predictive Biomarker in Solid Tumors, Cancer Discov. source

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  • May combine two claims.

    Premisecitation

    E. coli Nissle 1917 can be programmed to target tumor microenvironments and deliver CAR antigens and enhance CAR-T cell tumor cell killing.

    “Moreover, E. coli Nissle 1917 can be programmed to target tumor microenvironments and deliver CAR antigens and enhance CAR-T cell tumor cell killing.177”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [177] Vincent, 2023, Probiotic-guided CAR-T cells for solid tumor targeting, Science source

      Not checked in the free run.

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

    Interpretationnone given

    The impact of gut microbiota on melanoma systemic and cancer immunosurveillance is well established and will continue to have major clinical consequences.

    “The impact of the gut microbiota on melanoma systemic and cancer immunosurveillance is well established and will continue to have major clinical consequences.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    FMT from healthy donors may establish a healthy ecological network and reduce or eliminate harmful bacteria in the recipient.

    “FMT from healthy donor(s) may establish a healthy ecological network and minimize or eliminate harmful bacteria in the recipient.30”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [30] Routy, 2023, Fecal microbiota transplantation plus anti-PD-1 immunotherapy in advanced melanoma: a phase I trial, Nat. Med. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The peptidoglycan hydrolase SagA from Enterococcus faecium can be transferred into Lactococcus lactis to generate a probiotic strain that stimulates innate immune responses via NOD2 activation and promotes ICI antitumor activity in mice.

    “Thus, the peptidoglycan hydrolase SagA from Enterococcus faecium can be transferred into Lactococcus lactis to generate a probiotic strain that stimulates innate immune responses via NOD2 activation and promotes ICI antitumor activity in mice.26”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [26] Griffin, 2021, Enterococcus peptidoglycan remodeling promotes checkpoint inhibitor cancer immunotherapy, Science source

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  • May combine two claims.

    Premisecitation

    Cultivating microbes in bioreactors may generate spontaneous mutations, and gene flipping may change their function.

    “Moreover, cultivation of microbes in bioreactors may generate spontaneous mutations, and gene flipping may potentially change their function.163”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [163] Ramadas, 2010, Flipping DNA to generate and regulate microbial consortia, Genetics source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Even after successful engraftment, response can be prevented by tumor-intrinsic immune resistance, absence of necessary donor taxa, or failure to mount an effective immune response independent of microbiota.

    “Even with engraftment success, certain factors can prevent response, including immune resistance due to tumor-intrinsic factors, lack of necessary taxa in the donor sample, and failure to mount an efficient immune response regardless of microbiota.170”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [170] Porcari, 2023, Key determinants of success in fecal microbiota transplantation: From microbiome to clinic, Cell Host Microbe source

      Not checked in the free run.

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

    Interpretationnone given

    FMT or LBPs will likely affect the tumor microbiota, and these effects have not been well characterized.

    “Caution is needed, as FMT or LBPs will likely have consequences on the tumor microbiota that, to date, have not been well characterized.”
    Quote in the paperNot a substantial claim
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  • An FMT trial has two different identifiers

    Minor

    The paper gives NCT0498884 as an FMT trial identifier in two places, but later gives NCT04988841 for an advanced-melanoma FMT trial. The first identifier appears to be missing its final digit.

  • Point estimate falls outside its confidence interval

    Minor

    The reported estimate of 0.68% is below the stated 95% confidence interval, which begins at 0.75%.

2 of 2

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No citation lists for this paper yet — checked again daily.

References 183 · Cited by 89

Research works printed but not linked: 1

  1. Narayan, 2020, Mechanistic Biomarkers Informative of Both Cancer and Cardiovascular Disease: JACC State-of-the-Art Review, J. Am. Coll. Cardiol., 75, 2726, 10.1016/j.jacc.2020.03.067 · DOI

Authors
Routy, B., Jackson, T., Mählmann, L., Baumgartner, C. K., Blaser, M., Byrd, A., Corvaia, N., Couts, K., Davar, D., Derosa, L., Hang, H. C., Hospers, G., Isaksen, M., Kroemer, G., Malard, F., McCoy, K. D., Meisel, M., Pal, S., Ronai, Z., Segal, E., Sepich-Poore, G. D., Shaikh, F., Sweis, R. F., Trinchieri, G., van den Brink, M., Weersma, R. K., Whiteson, K., Zhao, L., McQuade, J., Zarour, H., & Zitvogel, L.
Affiliations
  • Centre Hospitalier de l’Université de Montréal (CA)
  • Melanoma Research Alliance (US)
  • Seerave Foundation (JE)
  • AbbVie (United States) (US)
  • Rutgers, The State University of New Jersey (US)
  • Genentech (US)
  • University of Colorado Anschutz (US)
  • University of Pittsburgh (US)
  • Inserm (FR)
  • University Medical Center Groningen (NL)
  • University of Calgary (CA)
  • City Of Hope National Medical Center (US)
  • Sanford Burnham Prebys Medical Discovery Institute (US)
  • Weizmann Institute of Science (IL)
  • Johns Hopkins University (US)
  • University of Chicago (US)
  • National Institutes of Health (US)
  • University of California, Irvine (US)
  • The University of Texas MD Anderson Cancer Center (US)
Corresponding author
  • McQuade, Jennifer
  • Zarour, Hassane
  • Zitvogel, Laurence
ORCID
Venue
Cancer Cell
Publisher
Elsevier BV
Published
2024-01
Volume
42
Issue
1
Pages
16-34
ISSN
1535-6108 (ISSN-L)
DOI
10.1016/j.ccell.2023.12.003
PMC
PMC11096984
OpenAlex
W4390350671
Cited by
89
References
183
Citations by year
2026: 27 · 2025: 44 · 2024: 17
FWCI
2.32
Type
journal article
Language
en
Open access
Licence
Locations
  • Cancer Cell (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • HAL (submittedVersion, other-oa)
  • University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, cc-by-nc-nd)
Funders
  • Agence Nationale de la Recherche (UMS3655)
  • National Cancer Institute
  • Ligue Contre le Cancer
  • Bristol-Myers Squibb
  • Institut National Du Cancer (16698, 19-CE15-0029-01, ANR-21-5 RHUS-0017)
  • Melanoma Research Alliance
  • Université Paris-Saclay
  • Association pour la Recherche sur le Cancer
  • Horizon 2020 (825410)
  • Seerave Foundation
  • National Institutes of Health (R01CA245292)
  • Labex Immuno-Oncology (ANR-18-IDEX-0001)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
  • Health Sciences › Medicine › Oncology › Cutaneous Melanoma Detection and Management
Keywords
melanoma, gut microbiota, cancer immunotherapy, immune checkpoint inhibitors, immune checkpoint inhibitor resistance, host-microbe interactions, microbiota modulation, microbial metabolites, patient stratification
MeSH terms
Gastrointestinal Microbiome, Host Microbial Interactions, Humans, Immunotherapy, Melanoma, Neoplasms, Microbiota

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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