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Microbiote intestinal et réponse aux inhibiteurs de points de contrôle

Does the composition of the gut microbiome influence the response of cancer patients to immune checkpoint inhibitors?

Searched on 15 November 2026

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How this review was searched

306 papers found, the 80 closest to the question screened on their abstract, 78 judged relevant, 30 included. Published from 2013 to 2024. 17 founding papers, 5 from the last three years, 11 reviews.

Published in a journal or proceedings: 30 · preprints: 0 · deposits nobody reviewed: 0. The conclusions of 13 open full texts were read too.

18 of the 18 findings are backed by a sentence found word for word in a paper. So are 6 of the 6 points of agreement, disagreement and gaps.

An exploratory synthesis, not a systematic review: the papers are read from their abstracts and the conclusions of their open full texts, and papers that OpenAlex and arXiv do not index, or that our searches word differently, can be missing.

Searches and sources

Inclusion: Include human and preclinical studies that assess gut microbial composition or its manipulation in relation to response, efficacy, or outcomes with immune checkpoint inhibitors, including proposed mechanisms and methods.

Key concepts: Gut microbiome composition, Cancer immunotherapy response, Immune checkpoint inhibitors, Proposed mechanisms, Study methods and settings

Queries:

  • gut microbiome checkpoint inhibitors
  • intestinal microbiota immunotherapy response
  • commensal bacteria anti-PD-1 anti-CTLA-4
  • microbiome metabolites T-cell activation
  • 16S sequencing metagenomics clinical cohorts
  • cancer types animal models clinical outcomes
  • OpenAlex, by relevance: 147
  • OpenAlex, last three years: 86
  • arXiv: 0
  • OpenAlex, reviews: 15
  • OpenAlex, most cited: 25
  • Cited by several of the closest papers: 50 (9 abstracts found on Semantic Scholar or arXiv)
  • Recent papers citing the founding ones: 25

A paper found by several searches is counted in each.

In short

La composition du microbiome intestinal est associée aux réponses aux inhibiteurs de points de contrôle immunitaire (ICI) dans plusieurs cancers : une diversité plus élevée et certains assemblages bactériens accompagnent souvent un bénéfice clinique, sans constituer une signature universelle. [2][3][5][8][13][21] Les expériences animales soutiennent un rôle causal de certains microbes et produits microbiens, capables de modifier l’activation immunitaire et l’activité antitumorale des ICI, mais ces mécanismes ne démontrent pas à eux seuls l’efficacité d’une intervention chez les patients. [11][14][18] Les associations dépendent des cohortes, des traitements et du moment du prélèvement ; les communautés microbiennes et leurs fonctions semblent donc plus informatives qu’une simple opposition entre bactéries bénéfiques et nuisibles. [21][25][27][30] L’alimentation, les antibiotiques et les probiotiques peuvent intervenir dans cette relation, mais les résultats fournis ne justifient pas une recommandation générale de supplémentation ou de transplantation pour améliorer les réponses aux ICI. [15][17][20][29] Tous les travaux fournis sont indiqués comme publiés dans des revues, et aucun comme prépublication ou dépôt non évalué ; les données humaines restent néanmoins largement observationnelles, tandis que les revues synthétisent surtout des résultats déjà produits. [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30]

This summary rests on the findings below, each with the sentences that support it.

Approaches compared

ApproachPapersStrengthsLimits
Comparer les microbiomes des patients selon leur bénéfice clinique [2][3][5][7][8][10][13][15][16][19][23] La répétition d’associations dans plusieurs cancers et populations soutient la pertinence clinique du microbiome au-delà d’un seul contexte.Ces comparaisons ne séparent pas complètement l’effet du microbiome de celui de l’état clinique, des traitements et des autres caractéristiques des patients.
Tester expérimentalement les voies microbiennes qui modulent l’immunité antitumorale [1][11][14][18] Les manipulations expérimentales permettent d’identifier des médiateurs et des voies causales plausibles, plutôt que de simples corrélations taxonomiques.Chaque mécanisme précis repose ici sur un travail particulier et sa transposition à une intervention sûre et efficace chez les patients reste à établir.
Passer des espèces isolées aux signatures communautaires et longitudinales [21][25][27][30] Ces approches évaluent la reproductibilité et prennent mieux en compte la structure écologique et la temporalité du microbiome.La validation d’une association ou d’un score ne démontre pas encore que son utilisation pour choisir une intervention améliore les résultats cliniques.
Examiner les facteurs modifiables : alimentation, antibiotiques et probiotiques [2][15][17] L’articulation entre expositions humaines et expériences animales permet d’explorer des leviers potentiellement accessibles.Les associations alimentaires humaines ne constituent pas un essai d’intervention, et les résultats sur des probiotiques particuliers ne s’étendent pas automatiquement à toutes les formulations.
Intégrer mécanismes, toxicités et perspectives de manipulation dans les revues [4][6][9][12][20][22][24][26][28][29] Les revues mettent en relation des résultats dispersés et rendent visibles les enjeux communs de mécanisme, de sécurité et de transférabilité.Elles ne constituent pas des réplications indépendantes des études qu’elles résument et leurs perspectives thérapeutiques ne valent pas démonstration d’efficacité clinique.

Comparer les microbiomes des patients selon leur bénéfice clinique

Des études menées dans le mélanome et plusieurs cancers épithéliaux, pulmonaires, rénaux, digestifs et hépatobiliaires comparent les microbiomes des patients bénéficiant ou non des ICI. Elles retrouvent des associations avec la diversité et l’abondance de certains taxons, mais les signatures diffèrent selon les cohortes et certaines études sont très petites.

  • Une diversité microbienne plus élevée est associée à des résultats favorables dans plusieurs cohortes, notamment pulmonaires et rénales, sans que cette association observationnelle établisse une causalité. [8][13]
    “Patients with high microbiome diversity had significantly prolonged progression-free survival when compared to those with low diversity.” [8]
    1 more supporting sentence
    “Greater microbial diversity was associated with clinical benefit from CPI therapy (p = 0.001), and multiple species were associated with clinical benefit or lack thereof.” [13]
  • Les associations taxonomiques concernent des ensembles différents selon les cancers, comme certains producteurs potentiels d’acides gras à chaîne courte dans les cancers digestifs ou des taxons associés à la survie dans les cancers hépatobiliaires. [16][19]
    “Gut bacteria that were capable of SCFA production, including Eubacterium, Lactobacillus, and Streptococcus, were positively associated with anti–PD-1/PD-L1 response across different GI cancer types.” [16]
    1 more supporting sentence
    “Among these taxa, patients with higher abundance of Lachnospiraceae bacterium-GAM79 and Alistipes sp Marseille-P5997, which were significantly enriched in the CBR group, achieved longer progression-free survival (PFS) and overall survival (OS) than patients with lower abundance.” [19]
  • Une étude sur le carcinome hépatocellulaire rapporte une signature microbienne associée à la survie dans une cohorte de validation, résultat encourageant mais encore propre à ce travail. [23]
    “In the validation cohort, better progression-free survival (PFS) and OS were noted in patients who had a preferable microbial signature in comparison with counter-group (PFS: 8.8 months vs 1.8 months; OS: not reached vs 6.5 months, both p<0.001).” [23]
  • La portée de certaines observations est limitée par leurs effectifs et leur sélection, l’étude japonaise rétrospective sur le cancer pulmonaire ne comprenant que 17 patients traités depuis plus de trois mois. [10]
    “In this retrospective study, we included 17 Japanese patients with advanced NSCLC who were treated with ICIs for >3 months in our hospital.” [10]

[2] Gut microbiome influences efficacy of PD-1–based immunotherapy against epitheli… (2017) · [3] Gut microbiome modulates response to anti–PD-1 immunotherapy in melanoma patien… (2017) · [5] The commensal microbiome is associated with anti–PD-1 efficacy in metastatic me… (2018) · [7] Gut microbiome affects the response to anti-PD-1 immunotherapy in patients with… (2019) · [8] The Diversity of Gut Microbiome is Associated With Favorable Responses to Anti–… (2019) · [10] The role of the gut microbiome on the efficacy of immune checkpoint inhibitors … (2019) · [13] Stool Microbiome Profiling of Patients with Metastatic Renal Cell Carcinoma Rec… (2020) · [15] The Gut Microbiome Associates with Immune Checkpoint Inhibition Outcomes in Pat… (2020) · [16] The Gut Microbiome Is Associated with Clinical Response to Anti–PD-1/PD-L1 Immu… (2020) · [19] Gut microbiome is associated with the clinical response to anti-PD-1 based immu… (2021) · [23] Gut microbiota and metabolites associate with outcomes of immune checkpoint inh… (2022)

Tester expérimentalement les voies microbiennes qui modulent l’immunité antitumorale

Les expériences explorent comment les bactéries, leurs métabolites et leurs composants influencent les cellules immunitaires et l’efficacité des traitements. Le travail fondateur sur les cellules myéloïdes ne porte pas sur les ICI, tandis que les études sur l’inosine, les acides gras à chaîne courte et le remodelage du peptidoglycane examinent directement le blocage des points de contrôle.

  • Dans une étude préclinique ne portant pas sur les ICI, la perturbation du microbiote réduit la réponse des cellules myéloïdes infiltrant les tumeurs à une immunothérapie par CpG et à une chimiothérapie au platine. [1]
    “In antibiotics-treated or germ-free mice, tumor-infiltrating myeloid-derived cells responded poorly to therapy, resulting in lower cytokine production and tumor necrosis after CpG-oligonucleotide treatment and deficient production of reactive oxygen species and cytotoxicity after chemotherapy.” [1]
  • Dans une étude chez la souris, l’inosine renforce l’activité antitumorale des lymphocytes T en présence d’immunothérapie et de stimuli pro-inflammatoires, ce qui indique un effet dépendant du contexte. [11]
    “In mouse models, inosine, together with proinflammatory stimuli and immunotherapy, strongly enhanced the antitumor capacities of T cells in multiple tumor types, including colorectal cancer, bladder cancer, and melanoma.” [11]
  • Une autre étude relie des concentrations sanguines élevées de butyrate et de propionate à la résistance au blocage de CTLA-4 et montre chez la souris une inhibition de plusieurs étapes de l’activation immunitaire. [14]
    “High blood butyrate and propionate levels are associated with resistance to CTLA-4 blockade and higher proportion of Treg cells.” [14]
  • Un mécanisme distinct, démontré dans une étude expérimentale, implique des fragments de peptidoglycane produits par l’activité enzymatique d’entérocoques et stimulant le récepteur immunitaire NOD2. [18]
    “This process results in the release of muramyl peptide fragments, which in turn act as stimulatory molecules to promote signaling of the innate immune sensor protein NOD2 and improved immunotherapy responses.” [18]

[1] Commensal Bacteria Control Cancer Response to Therapy by Modulating the Tumor M… (2013) · [11] Microbiome-derived inosine modulates response to checkpoint inhibitor immunothe… (2020) · [14] Systemic short chain fatty acids limit antitumor effect of CTLA-4 blockade in h… (2020) · [18] Enterococcus peptidoglycan remodeling promotes checkpoint inhibitor cancer immu… (2021)

Passer des espèces isolées aux signatures communautaires et longitudinales

Ces travaux combinent analyses intercohortes, apprentissage automatique, réseaux de co-abondance et prélèvements répétés pour construire des signatures plus robustes. Ils montrent que la réponse est liée à l’organisation des communautés et à leur évolution pendant le traitement, tout en soulignant les difficultés de généralisation.

  • L’analyse intercohortes du mélanome confirme une association globale avec les résultats des ICI, mais ne retrouve aucune espèce constituant un biomarqueur pleinement constant entre études. [21]
    “Accordingly, a panel of species, including Bifidobacterium pseudocatenulatum, Roseburia spp. and Akkermansia muciniphila, associated with responders was identified, but no single species could be regarded as a fully consistent biomarker across studies.” [21]
  • Une autre analyse intégrée du mélanome relie la répartition géographique non uniforme des communautés microbiennes à une partie des différences entre cohortes. [25]
    “Gut microbial communities (microbiotypes) with nonuniform geographical distribution were associated with favorable and unfavorable outcomes, contributing to discrepancies between cohorts.” [25]
  • Une étude méthodologique développe un score écologique combinant réseaux microbiens et quantification d’Akkermansia, puis le valide dans des cohortes supplémentaires pulmonaires et génito-urinaires. [27]
    “When combined with the quantification of Akkermansia species, this procedure allowed a person-based calculation of a topological score (TOPOSCORE) that was validated in an additional 254 NSCLC patients and in 216 genitourinary cancer patients.” [27]
  • Dans une étude longitudinale du mélanome, davantage de signatures discriminantes apparaissent uniquement après le début du traitement qu’uniquement à l’inclusion, montrant les limites d’un prélèvement initial isolé. [30]
    “Out of 99 SGBs that could discriminate between these two groups, 20 were differentially abundant only at baseline, while 42 were differentially abundant only after treatment initiation.” [30]

[21] Cross-cohort gut microbiome associations with immune checkpoint inhibitor respo… (2022) · [25] Intestinal microbiota signatures of clinical response and immune-related advers… (2022) · [27] Custom scoring based on ecological topology of gut microbiota associated with c… (2024) · [30] Longitudinal gut microbiome changes in immune checkpoint blockade-treated advan… (2024)

Examiner les facteurs modifiables : alimentation, antibiotiques et probiotiques

Les observations sur les antibiotiques et l’étude combinant données alimentaires humaines et expériences animales suggèrent que des expositions modifiables peuvent infléchir la relation entre microbiome et ICI. Les effets ne se résument toutefois pas à augmenter les bactéries réputées bénéfiques, puisque l’usage de probiotiques commerciaux n’apparaît pas systématiquement favorable.

  • Dans une cohorte japonaise de cancer pulmonaire, l’exposition aux antibiotiques avant les ICI est associée à une diversité initiale plus faible et à la sous-représentation de certains taxons. [15]
    “Patients who received pre-ICI antibiotic had lower alpha diversity at baseline and underrepresentation of Ruminococcaceae UCG 13 and Agathobacter.” [15]
  • Dans l’unique étude alimentaire fournie, une consommation plus élevée de fibres est associée à une meilleure survie sans progression chez 128 patients atteints de mélanome, avec le bénéfice le plus marqué en l’absence de probiotiques. [17]
    “Higher dietary fiber was associated with significantly improved progression-free survival in 128 patients on ICB, with the most pronounced benefit observed in patients with sufficient dietary fiber intake and no probiotic use.” [17]
  • Dans les expériences animales parallèles de cette même étude, un régime pauvre en fibres ou l’administration de probiotiques altèrent la réponse aux traitements fondés sur les anti-PD-1. [17]
    “Findings were recapitulated in preclinical models, which demonstrated impaired treatment response to anti–programmed cell death 1 (anti–PD-1)–based therapy in mice receiving a low-fiber diet or probiotics, with a lower frequency of interferon-γ–positive cytotoxic T cells in the tumor microenvironment.” [17]

[2] Gut microbiome influences efficacy of PD-1–based immunotherapy against epitheli… (2017) · [15] The Gut Microbiome Associates with Immune Checkpoint Inhibition Outcomes in Pat… (2020) · [17] Dietary fiber and probiotics influence the gut microbiome and melanoma immunoth… (2021)

Intégrer mécanismes, toxicités et perspectives de manipulation dans les revues

Les revues rassemblent les voies reliant microbiote, immunité innée et adaptative, métabolites et microenvironnement tumoral, ainsi que les possibilités de modulation du microbiome. Elles soulignent aussi que les signatures de bénéfice et de toxicité peuvent se recouper et que l’hétérogénéité clinique et méthodologique freine l’application en routine.

  • Les revues proposent que le microbiote modifie l’efficacité des ICI par des interactions avec les cellules immunitaires et par des métabolites capables d’agir au-delà de l’intestin. [24]
    “Deciphering the underlying mechanisms reveals that the gut microbiota reprogram the immunity of the tumor microenvironment (TME) by engaging innate and/or adaptive immune cells.” [24]
  • Une revue souligne que des bactéries associées à une meilleure sensibilité aux ICI peuvent également être associées à davantage d’effets indésirables immunitaires, ce qui impose d’examiner conjointement efficacité et sécurité. [20]
    “Emerging data have shown that certain bacterial strains, such as Faecalibacterium that confer sensitivity to ICPI, also have a higher propensity to increase the risk of irAEs.” [20]
  • Les revues constatent une faible concordance entre les bactéries favorables identifiées et recommandent une standardisation des prélèvements, du séquençage et des analyses. [6][9]
    “While the investigations all exhibit interesting results and conclusions, we find little congruence in the specific bacteria that were found favorable for antitumor responses.” [6]
    1 more supporting sentence
    “Among these, a better understanding of the immunomodulatory function of the microbiome, standardization in sampling, sequencing techniques, and data analysis, and ensuring uniformity across various aspects of study design are warranted in conducting future prospective studies seeking to validate the gut microbiome as a potential biomarker of response to checkpoint blockade.” [9]

[4] Gut microbiome modulates efficacy of immune checkpoint inhibitors (2018) · [6] The gut microbiota and immune checkpoint inhibitors (2018) · [9] The gut microbiome and response to immune checkpoint inhibitors: preclinical an… (2019) · [12] Modulatory effects of gut microbiome in cancer immunotherapy: A novel paradigm … (2020) · [20] The role of gut microbiome in modulating response to immune checkpoint inhibito… (2021) · [22] Gut microbiome in modulating immune checkpoint inhibitors (2022) · [24] Gut microbiota influence immunotherapy responses: mechanisms and therapeutic st… (2022) · [26] Critical role of the gut microbiota in immune responses and cancer immunotherapy (2024) · [28] Gut microbiota reshapes cancer immunotherapy efficacy: Mechanisms and therapeut… (2024) · [29] Insights into the Relationship Between the Gut Microbiome and Immune Checkpoint… (2024)

Where the papers agree

What they leave open

Often cited, not read

Several of the papers found cite these works, but no abstract of them could be found: they are not in the synthesis. Read them if they are not already known to you.

References

  1. [1] Commensal Bacteria Control Cancer Response to Therapy by Modulating the Tumor Microenvironment

    Noriho Iida, Amiran Dzutsev, C. Andrew Stewart, Loretta Smith et al. · 2013 · Science · cited 2290 times · doi:10.1126/science.1240527

    Founding perturbation microbienne chez la souris · experiment

    Why it is here: Montre expérimentalement qu’une perturbation du microbiote réduit l’efficacité de traitements anticancéreux, par l’altération des fonctions myéloïdes tumorales.

    Abstract

    The gut microbiota influences both local and systemic inflammation. Inflammation contributes to development, progression, and treatment of cancer, but it remains unclear whether commensal bacteria affect inflammation in the sterile tumor microenvironment. Here, we show that disruption of the microbiota impairs the response of subcutaneous tumors to CpG-oligonucleotide immunotherapy and platinum chemotherapy. In antibiotics-treated or germ-free mice, tumor-infiltrating myeloid-derived cells responded poorly to therapy, resulting in lower cytokine production and tumor necrosis after CpG-oligonucleotide treatment and deficient production of reactive oxygen species and cytotoxicity after chemotherapy. Thus, optimal responses to cancer therapy require an intact commensal microbiota that mediates its effects by modulating myeloid-derived cell functions in the tumor microenvironment. These findings underscore the importance of the microbiota in the outcome of disease treatment.

  2. [2] Gut microbiome influences efficacy of PD-1–based immunotherapy against epithelial tumors

    Bertrand Routy, Emmanuelle Le Chatelier, Lisa Derosa, Connie P.M. Duong et al. · 2017 · Science · cited 5879 times · doi:10.1126/science.aan3706

    Founding études cliniques et modèles murins · observational study

    Why it is here: Rapporte des associations entre microbiote, antibiotiques et réponse au blocage de PD-1, ainsi qu’une restauration préclinique par Akkermansia.

    Abstract

    Good bacteria help fight cancer Resident gut bacteria can affect patient responses to cancer immunotherapy (see the Perspective by Jobin). Routy et al. show that antibiotic consumption is associated with poor response to immunotherapeutic PD-1 blockade. They profiled samples from patients with lung and kidney cancers and found that nonresponding patients had low levels of the bacterium Akkermansia muciniphila . Oral supplementation of the bacteria to antibiotic-treated mice restored the response to immunotherapy. Matson et al. and Gopalakrishnan et al. studied melanoma patients receiving PD-1 blockade and found a greater abundance of “good” bacteria in the guts of responding patients. Nonresponders had an imbalance in gut flora composition, which correlated with impaired immune cell activity. Thus, maintaining healthy gut flora could help patients combat cancer. Science , this issue p. 91 , p. 104 , p. 97 ; see also p. 32

  3. [3] Gut microbiome modulates response to anti–PD-1 immunotherapy in melanoma patients

    Vancheswaran Gopalakrishnan, C. N. Spencer, Luigi Nezi, Alexandre Reuben et al. · 2017 · Science · cited 4968 times · doi:10.1126/science.aan4236

    Founding cohorte clinique et modèles murins · observational study

    Why it is here: Décrit les liens entre composition intestinale et réponse anti-PD-1 dans le mélanome, avec des résultats précliniques complémentaires.

    Abstract

    Good bacteria help fight cancer Resident gut bacteria can affect patient responses to cancer immunotherapy (see the Perspective by Jobin). Routy et al. show that antibiotic consumption is associated with poor response to immunotherapeutic PD-1 blockade. They profiled samples from patients with lung and kidney cancers and found that nonresponding patients had low levels of the bacterium Akkermansia muciniphila . Oral supplementation of the bacteria to antibiotic-treated mice restored the response to immunotherapy. Matson et al. and Gopalakrishnan et al. studied melanoma patients receiving PD-1 blockade and found a greater abundance of “good” bacteria in the guts of responding patients. Nonresponders had an imbalance in gut flora composition, which correlated with impaired immune cell activity. Thus, maintaining healthy gut flora could help patients combat cancer. Science , this issue p. 91 , p. 104 , p. 97 ; see also p. 32

  4. [4] Gut microbiome modulates efficacy of immune checkpoint inhibitors

    Ming Yi, Shengnan Yu, Shuang Qin, Qian Liu et al. · 2018 · Journal of Hematology & Oncology · cited 188 times · doi:10.1186/s13045-018-0592-6

    Founding Review revue des mécanismes microbiens · review

    Why it is here: Elle examine comment la diversité et les bactéries intestinales modulent l’efficacité des ICI et leurs mécanismes possibles.

    Abstract · conclusions of the full text read too

    Immune checkpoint inhibitors (ICIs) therapy is a novel strategy for cancer treatments in recent years. However, it was observed that most patients treated with ICIs could not get benefit from the therapy, which led to the limitation of clinical application. Motivated by potent and durable efficacy of ICIs, oncologists endeavor to explore the mechanisms of resistance to ICIs and increase the drug sensitivity. It is known that heterogeneity of gut microbiome in populations may result in different outcomes of therapy. In xenograft model, bacteria in gut have been proved as a crucial factor regulating immunotherapy efficacy. And the similar phenomenon was obtained in patients. In this review, we summarized relevant advancements about gut microbiome and ICIs. Furthermore, we focused on modulatory function of gut microbiome in ICIs therapy and possible antitumor mechanism of specific commensals in ICIs treatment. We propose that gut microbiome is an important predictive factor, and manipulation of gut microbiome is feasible to elevate response rate in ICIs therapy.

  5. [5] The commensal microbiome is associated with anti–PD-1 efficacy in metastatic melanoma patients

    Vyara Z. Matson, Jessica L. Fessler, Riyue Bao, Tara Chongsuwat et al. · 2018 · Science · cited 3179 times · doi:10.1126/science.aao3290

    Founding cohorte clinique et modèles murins · observational study

    Why it is here: Apporte des données sur les signatures microbiennes associées à la réponse anti-PD-1 dans le mélanome et des preuves précliniques connexes.

    Abstract

    Good bacteria help fight cancer Resident gut bacteria can affect patient responses to cancer immunotherapy (see the Perspective by Jobin). Routy et al. show that antibiotic consumption is associated with poor response to immunotherapeutic PD-1 blockade. They profiled samples from patients with lung and kidney cancers and found that nonresponding patients had low levels of the bacterium Akkermansia muciniphila . Oral supplementation of the bacteria to antibiotic-treated mice restored the response to immunotherapy. Matson et al. and Gopalakrishnan et al. studied melanoma patients receiving PD-1 blockade and found a greater abundance of “good” bacteria in the guts of responding patients. Nonresponders had an imbalance in gut flora composition, which correlated with impaired immune cell activity. Thus, maintaining healthy gut flora could help patients combat cancer. Science , this issue p. 91 , p. 104 , p. 97 ; see also p. 32

  6. [6] The gut microbiota and immune checkpoint inhibitors

    Audrey Humphries, ADIL I. DAUD · 2018 · Human Vaccines & Immunotherapeutics · cited 42 times · doi:10.1080/21645515.2018.1442970

    Review synthèse des études précliniques et cliniques · review

    Why it is here: La revue examine le lien entre microbiote intestinal et efficacité des inhibiteurs de points de contrôle, tout en soulignant les divergences entre études.

    Abstract

    Although immunotherapy has been remarkably effective across multiple cancer types, there continues to be a significant number of non-responding patients. A possible factor proposed to influence the efficacy of immunotherapies is the gut microbiome. We discuss the results and implications of recent research on the relationship between the gut microbiome, our immune systems, and immune checkpoint inhibitor therapies including anti-CTLA-4 Ab and anti-PD-1 Ab. While the investigations all exhibit interesting results and conclusions, we find little congruence in the specific bacteria that were found favorable for antitumor responses. It is unclear whether the inconsistencies are due to differential approaches in study design (pre-clinical or clinical subjects, anti-CTLA-4 Ab or anti-PD-1 Ab), experimental methods and measurements (metagenomics sequencing and clustering variations) or subject population dynamics (differential cancer types and baseline characteristics). Moreover, we note studies regarding particular bacterial commensals and autoimmune diseases, which challenge findings from these investigations. We conclude that with the current research, clinical investigators can appreciate the critical role of gut microbiota in mediating immunostimulant response. However, prospective research exploring the biochemical mechanisms which commensal bacteria communicate with each other and the immune system is imperative to understand how they can be adjusted properly for higher immunotherapy response.

  7. [7] Gut microbiome affects the response to anti-PD-1 immunotherapy in patients with hepatocellular carcinoma

    Yi Zheng, Tingting Wang, Xiaoxuan Tu, Yun Huang et al. · 2019 · Journal for ImmunoTherapy of Cancer · cited 570 times · doi:10.1186/s40425-019-0650-9

    Founding profilage métagénomique longitudinal · observational study

    Why it is here: Relie les changements et la diversité du microbiote aux réponses au traitement anti-PD-1 du carcinome hépatocellulaire.

    Abstract · conclusions of the full text read too

    BACKGROUND: Checkpoint-blockade immunotherapy targeting programmed cell death protein 1 (PD-1) has recently shown promising efficacy in hepatocellular carcinoma (HCC). However, the factors affecting and predicting the response to anti-PD-1 immunotherapy in HCC are still unclear. Herein, we report the dynamic variation characteristics and specificities of the gut microbiome during anti-PD-1 immunotherapy in HCC using metagenomic sequencing. RESULTS: Fecal samples from patients responding to immunotherapy showed higher taxa richness and more gene counts than those of non-responders. For dynamic analysis during anti-PD-1 immunotherapy, the dissimilarity of beta diversity became prominent across patients as early as Week 6. In non-responders, Proteobacteria increased from Week 3, and became predominant at Week 12. Twenty responder-enriched species, including Akkermansia muciniphila and Ruminococcaceae spp., were further identified. The related functional genes and metabolic pathway analysis, such as carbohydrate metabolism and methanogenesis, verified the potential bioactivities of responder-enriched species. CONCLUSIONS: Gut microbiome may have a critical impact on the responses of HCC patients treated with anti-PD-1 immunotherapy. The dynamic variation characteristics of the gut microbiome may provide early predictions of the outcomes of immunotherapy in HCC, which is critical for disease-monitoring and treatment decision-making.

  8. [8] The Diversity of Gut Microbiome is Associated With Favorable Responses to Anti–Programmed Death 1 Immunotherapy in Chinese Patients With NSCLC

    Yueping Jin, Hui Dong, Liliang Xia, Yi Yang et al. · 2019 · Journal of Thoracic Oncology · cited 597 times · doi:10.1016/j.jtho.2019.04.007

    Founding suivi clinique et séquençage 16S · observational study

    Why it is here: L’étude suit des patients atteints de cancer pulmonaire et évalue la diversité microbienne en lien avec les résultats du nivolumab.

    Abstract

    INTRODUCTION Gut microbiome affecting the responses to immune checkpoint inhibitors against advanced NSCLC has been investigated in the Western population. However, considering pre-existing genetic and gut microbiota variation, the relevance remains unknown in the East-Asian NSCLC population. This study is designed to explore the relationship between gut microbiome and clinical outcomes in Chinese patients with NSCLC who have received treatment using an anti-programmed death 1 (PD-1) blockade. METHODS Thirty-seven patients with advanced NSCLC receiving treatment with nivolumab were enrolled in CheckMate 078 (NCT02613507) and CheckMate 870 (NCT03195491). Fecal samples were collected at the starting point, when patients received nivolumab, at clinical evaluation, and when disease progression was noted. 16S ribosome RNA gene sequencing was applied to assess gut microbiota profiles. Peripheral immune signatures were determined by multicolor flow cytometry in parallel. RESULTS When subgrouping patients into responder (R) and nonresponder according to the clinical response assessed using Response Evaluation Criteria in Solid Tumor version 1.1, R patients harbored higher diversity of gut microbiome at the starting point with stable composition during the treatment. Patients with high microbiome diversity had significantly prolonged progression-free survival when compared to those with low diversity. Compositional difference was observed between the two groups as well with the enrichment of Alistipes putredinis, Bifidobacterium longum, and Prevotella copri in R whereas Ruminococcus_unclassified enriched in nonresponding patients. Analysis of systemic immune responses using multicolor flow cytometry revealed that patients with a high abundance of microbiome diversity in the gut had a greater frequency of unique memory CD8+ T cell and natural killer cell subsets in the periphery in response to anti-PD-1 therapy. CONCLUSIONS Our results reveal strong correlation between gut microbiome diversity and the responses to anti-PD-1 immunotherapy in Chinese patients with advanced NSCLC. Patients with favorable gut microbiome (such as those with high diversity) exhibit enhanced memory T cell and natural killer cell signatures in the periphery. These findings provide important implications for the prediction and the evaluation of anti-PD-1 immunotherapy against NSCLC in the Chinese population.

  9. [9] The gut microbiome and response to immune checkpoint inhibitors: preclinical and clinical strategies

    Jun Gong, Alex Chehrazi‐Raffle, Veronica Placencio-Hickok, Michelle Guan et al. · 2019 · Clinical and Translational Medicine · cited 115 times · doi:10.1186/s40169-019-0225-x

    Founding Review synthèse des études cliniques et précliniques · review

    Why it is here: La revue rassemble les résultats sur le microbiote comme biomarqueur et sur son lien avec l’efficacité antitumorale des ICI.

    Abstract · conclusions of the full text read too

    There is growing interest in identifying predictive biomarkers for inhibitors of programmed cell death protein 1 receptor (PD-1), programmed death ligand 1 (PD-L1), and cytotoxic T-lymphocyte associated protein 4 (CTLA-4). Given the links between the stool microbiota, anticancer immunosurveillance, and general health, the composition of the gut microbiome has recently undergone investigation as a biomarker for immunotherapy. In this review, we highlight published results from preclinical and clinical studies to date supporting a relationship between the gut microbiome and antitumor efficacy of immune checkpoint inhibitors. Despite the promising and hypothesis-generating findings that have been produced in this arena to date, there remain some inconsistencies amongst present data that may need to be resolved to contribute to further development. Among these, a better understanding of the immunomodulatory function of the microbiome, standardization in sampling, sequencing techniques, and data analysis, and ensuring uniformity across various aspects of study design are warranted in conducting future prospective studies seeking to validate the gut microbiome as a potential biomarker of response to checkpoint blockade.

  10. [10] The role of the gut microbiome on the efficacy of immune checkpoint inhibitors in Japanese responder patients with advanced non-small cell lung cancer

    Yuki Katayama, Tadaaki Yamada, Takayuki Shimamoto, Masahiro Iwasaku et al. · 2019 · Translational Lung Cancer Research · cited 99 times · doi:10.21037/tlcr.2019.10.23

    Founding séquençage 16S chez des patients · observational study

    Why it is here: Cette étude clinique compare le microbiote de patients japonais atteints de cancer pulmonaire selon leur réponse aux ICI.

    Abstract · conclusions of the full text read too

    BACKGROUND: Cancer immunotherapy is being developed as a promising alternative for advanced non-small cell lung cancer (NSCLC). However, novel biomarkers are required to select patients that will benefit from treatment with immune checkpoint inhibitors (ICIs) for a long period of time. The gut microbiome is expected to be a promising biomarker of ICI response owing to the regulation of the immune status within the host. METHODS: In this retrospective study, we included 17 Japanese patients with advanced NSCLC who were treated with ICIs for >3 months in our hospital. Fecal samples obtained from the patients during ICI treatment were analyzed by 16S ribosomal RNA gene sequencing. We examined the correlation between the diversity of the gut microbiome and treatment with ICIs. RESULTS: Several bacterial species were more abundant in ICI responders than in non-responders. Patients with abundant Lactobacillus and Clostridium tended to have a longer time to treatment failure (TTF) after receiving ICI than those with a lower abundance. CONCLUSIONS: In conclusion, the composition of the gut microbiome is associated with better clinical benefits from ICI treatment in Japanese patients with NSCLC. A further large-scale study is warranted to validate the composition of the gut microbiome as a novel clinical factor influencing the response to ICIs for an extended time in NSCLC.

  11. [11] Microbiome-derived inosine modulates response to checkpoint inhibitor immunotherapy

    Lukas Franz Mager, Regula Burkhard, Nicola Pett, Noah C.A. Cooke et al. · 2020 · Science · cited 1461 times · doi:10.1126/science.abc3421

    Founding études mécanistiques chez la souris · experiment

    Why it is here: Montre qu’un métabolite produit par certaines bactéries peut renforcer l’immunité antitumorale et l’effet du blocage des points de contrôle.

    Abstract

    Inosine modulates antitumor immunity Checkpoint blockade immunotherapy harnesses the immune system to kill cancer cells and has been used with great success to treat certain tumors, but not all cancer patients respond. The efficacy of checkpoint blockade immunotherapy has been shown to depend on the presence of distinct, beneficial bacteria residing in the gut of patients, but how the microbiome mediates such beneficial effects is unclear. Mager et al. found that specific bacteria produce a metabolite called inosine that enhances the effect of checkpoint blockade immunotherapy (see the Perspective by Shaikh and Sears). In mouse models, inosine, together with proinflammatory stimuli and immunotherapy, strongly enhanced the antitumor capacities of T cells in multiple tumor types, including colorectal cancer, bladder cancer, and melanoma. Science , this issue p. 1481 ; see also p. 1427

  12. [12] Modulatory effects of gut microbiome in cancer immunotherapy: A novel paradigm for blockade of immune checkpoint inhibitors

    Sama Rezasoltani, Abbas Yadegar, Hamid Asadzadeh Aghdaei, Mohammad Reza Zali · 2020 · Cancer Medicine · cited 69 times · doi:10.1002/cam4.3694

    Review revue des interactions microbiote-ICI · review

    Why it is here: Elle examine comment le microbiote peut renforcer l’action des ICI et influencer l’immunité antitumorale.

    Abstract

    The human gastrointestinal (GI) tract harbors gut microbiome, which plays a crucial role in preserving homeostasis at the intestinal host-microbial interface. Conversely, specific gut microbiota may be altered during various pathological conditions and produce a number of toxic compounds and oncoproteins, in turn, to induce both inflammatory response and carcinogenesis. Recently, promising findings have been documented toward the implementation of certain intestinal microbiome in the next era of cancer biology and cancer immunotherapy. Notably, intestinal microbiota can cooperate with immune checkpoint inhibitors (ICIs) of its host, especially in enhancing the efficacy of programmed death 1 (PD-1) protein and its ligand programmed death ligand 1 (PD-L1) blockade therapy for cancer. Herein, we review the dual function of gut microbiota in triggering GI cancers, its association with host immunity and its beneficial functions in modulation of cancer immunotherapy responses. Furthermore, we consider the significance of gut microbiota as a potential biomarker for predicting the efficacy of cancer immunotherapy. Finally, we summarize the relevant limitations that affect the effectiveness and clinical applications of gut microbiome in response to immunotherapy.

  13. [13] Stool Microbiome Profiling of Patients with Metastatic Renal Cell Carcinoma Receiving Anti–PD-1 Immune Checkpoint Inhibitors

    Nicholas Salgia, Paulo Gustavo Bergerot, Manuel Caitano Maia, Nazlı Dizman et al. · 2020 · European Urology · cited 198 times · doi:10.1016/j.eururo.2020.07.011

    Founding profilage longitudinal des selles · observational study

    Why it is here: Associe diversité et changements d’espèces du microbiote aux bénéfices cliniques des inhibiteurs chez des patients atteints de cancer rénal.

    Abstract

    Preclinical models and early clinical data suggest an interplay between the gut microbiome and response to immunotherapy in solid tumors including metastatic renal cell carcinoma (mRCC). We sought to characterize the stool microbiome of mRCC patients receiving a checkpoint inhibitor (CPI) and to assess treatment-related changes in microbiome composition over the course of CPI therapy. Stool was collected from 31 patients before initiation of nivolumab (77%) or nivolumab plus ipilimumab (23%) therapy, of whom 58% experienced clinical benefit. Greater microbial diversity was associated with clinical benefit from CPI therapy (p = 0.001), and multiple species were associated with clinical benefit or lack thereof. Temporal profiling of the microbiome indicated that the relative abundance of Akkermansia muciniphila increased in patients deriving clinical benefit from CPIs. This study substantiates results from previous CPI-related microbiome profiling studies in mRCC. Temporal changes in microbiome composition suggest potential utility in modulating the microbiome for more successful CPI outcomes. PATIENT SUMMARY: We compared the composition and diversity of the gut microbiome in patients receiving immunotherapy for renal cell carcinoma. We found that higher microbial diversity is associated with better treatment outcomes. Treatment response is characterized by changes in microbial species over the course of treatment.

  14. [14] Systemic short chain fatty acids limit antitumor effect of CTLA-4 blockade in hosts with cancer

    Clélia Coutzac, Jean-Mehdi Jouniaux, Angélo Paci, Julien Schmidt et al. · 2020 · Nature Communications · cited 545 times · doi:10.1038/s41467-020-16079-x

    Founding étude clinique et expérimentation murine · experiment

    Why it is here: Relie les acides gras à chaîne courte à une moindre efficacité du blocage de CTLA-4 et en propose un mécanisme immunitaire.

    Abstract

    Gut microbiota composition influences the clinical benefit of immune checkpoints in patients with advanced cancer but mechanisms underlying this relationship remain unclear. Molecular mechanism whereby gut microbiota influences immune responses is mainly assigned to gut microbial metabolites. Short-chain fatty acids (SCFA) are produced in large amounts in the colon through bacterial fermentation of dietary fiber. We evaluate in mice and in patients treated with anti-CTLA-4 blocking mAbs whether SCFA levels is related to clinical outcome. High blood butyrate and propionate levels are associated with resistance to CTLA-4 blockade and higher proportion of Treg cells. In mice, butyrate restrains anti-CTLA-4-induced up-regulation of CD80/CD86 on dendritic cells and ICOS on T cells, accumulation of tumor-specific T cells and memory T cells. In patients, high blood butyrate levels moderate ipilimumab-induced accumulation of memory and ICOS + CD4 + T cells and IL-2 impregnation. Altogether, these results suggest that SCFA limits anti-CTLA-4 activity.

  15. [15] The Gut Microbiome Associates with Immune Checkpoint Inhibition Outcomes in Patients with Advanced Non–Small Cell Lung Cancer

    Taiki Hakozaki, Corentin Richard, Arielle Elkrief, Yukio Hosomi et al. · 2020 · Cancer Immunology Research · cited 350 times · doi:10.1158/2326-6066.cir-20-0196

    Founding cohorte prospective et séquençage 16S · observational study

    Why it is here: Analyse les associations entre microbiote initial, antibiotiques et résultats des inhibiteurs chez des patients atteints de cancer pulmonaire.

    Abstract

    Abstract The gut microbiome (GM) plays an important role in shaping systemic immune responses and influences immune checkpoint inhibitor (ICI) efficacy. Antibiotics worsen clinical outcomes in patients receiving ICI. However, whether GM profiling and baseline antibiotic can be a biomarker of ICI efficacy in advanced non–small cell lung cancer (NSCLC) remains unknown. We prospectively collected baseline (pre-ICI) fecal samples and clinical data of 70 Japanese patients suffering from advanced NSCLC and treated them with anti–PD-1/PD-L1 antibodies as a first-line or treatment-refractory therapy. We performed 16S rRNA V3–V4 sequencing of gene amplicons of fecal samples, and bacteria diversity and differential abundance analysis was performed. The clinical endpoints were objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and immune-related adverse events (irAE). ORR was 34%, and median PFS and OS were 5.2 and 16.2 months, respectively. Patients who received pre-ICI antibiotic had lower alpha diversity at baseline and underrepresentation of Ruminococcaceae UCG 13 and Agathobacter. When analyzing antibiotic-free patients, alpha diversity correlated with OS. In addition, Ruminococcaceae UCG 13 and Agathobacter were enriched in patients with favorable ORR and PFS >6 months. Ruminococcaceae UCG 13 was enriched in patients with OS >12 months. GM differences were observed between patients who experienced low- versus high-grade irAE. We demonstrated the negative influence of antibiotic on the GM composition and identified the bacteria repertoire in patients experiencing favorable responses to ICI. See articles by Tomita et al., p. 1236, and Peng et al., p. 1251

  16. [16] The Gut Microbiome Is Associated with Clinical Response to Anti–PD-1/PD-L1 Immunotherapy in Gastrointestinal Cancer

    Zhi Peng, Siyuan Cheng, Yan Kou, Ziqi Wang et al. · 2020 · Cancer Immunology Research · cited 383 times · doi:10.1158/2326-6066.cir-19-1014

    Founding étude clinique avec séquençage 16S · observational study

    Why it is here: Cette étude humaine associe des profils microbiens fécaux à la réponse aux anti-PD-1/PD-L1 dans les cancers gastro-intestinaux.

    Abstract

    Abstract We report on a comprehensive analysis of the gut microbiomes of patients with gastrointestinal (GI) cancer receiving anti–PD-1/PD-L1 treatment. The human gut microbiota has been associated with clinical responses to anti–PD-1/PD-L1 immunotherapy in melanoma, non–small cell lung cancer, and renal cell carcinoma. We aimed to investigate this association in GI cancers. We also identified bacterial taxa with patient stratification potential. We recruited 74 patients with advanced-stage GI cancer receiving anti–PD-1/PD-L1 treatment and collected their fecal samples prior to and during immunotherapy, along with clinical evaluations. Our 16S rRNA taxonomy survey on the fecal samples revealed an elevation of the Prevotella/Bacteroides ratio in patients, with a preferred response to anti–PD-1/PD-L1 treatment, and a particular subgroup of responders harboring a significantly higher abundance of Prevotella, Ruminococcaceae, and Lachnospiraceae. The shotgun metagenomes of the same samples showed that patients exhibiting different responses had differential abundance of pathways related to nucleoside and nucleotide biosynthesis, lipid biosynthesis, sugar metabolism, and fermentation to short-chain fatty acids (SCFA). Gut bacteria that were capable of SCFA production, including Eubacterium, Lactobacillus, and Streptococcus, were positively associated with anti–PD-1/PD-L1 response across different GI cancer types. We further demonstrated that the identified bacterial taxa were predictive of patient stratification in both our cohort and melanoma patients from two previously published studies. Our results thus highlight the impact of gut microbiomes on anti–PD-1/PD-L1 outcomes, at least in a subset of patients with GI cancer, and suggest the potential of the microbiome as a marker for immune-checkpoint blockade responses. See articles by Tomita et al., p. 1236, and Hakozaki et al., p. 1243

  17. [17] Dietary fiber and probiotics influence the gut microbiome and melanoma immunotherapy response

    Christine N. Spencer, Jennifer Leigh McQuade, Vancheswaran Gopalakrishnan, John A. McCulloch et al. · 2021 · Science · cited 1034 times · doi:10.1126/science.aaz7015

    Founding cohorte et modèles précliniques · experiment

    Why it is here: Relie alimentation, probiotiques et microbiote à la réponse aux inhibiteurs de PD-1 chez des patients atteints de mélanome et chez la souris.

    Abstract

    Gut bacteria modulate the response to immune checkpoint blockade (ICB) treatment in cancer, but the effect of diet and supplements on this interaction is not well studied. We assessed fecal microbiota profiles, dietary habits, and commercially available probiotic supplement use in melanoma patients and performed parallel preclinical studies. Higher dietary fiber was associated with significantly improved progression-free survival in 128 patients on ICB, with the most pronounced benefit observed in patients with sufficient dietary fiber intake and no probiotic use. Findings were recapitulated in preclinical models, which demonstrated impaired treatment response to anti–programmed cell death 1 (anti–PD-1)–based therapy in mice receiving a low-fiber diet or probiotics, with a lower frequency of interferon-γ–positive cytotoxic T cells in the tumor microenvironment. Together, these data have clinical implications for patients receiving ICB for cancer.

  18. [18] Enterococcus peptidoglycan remodeling promotes checkpoint inhibitor cancer immunotherapy

    Matthew E. Griffin, Juliel Espinosa, Jessica L. Becker, Ji‐Dung Luo et al. · 2021 · Science · cited 375 times · doi:10.1126/science.abc9113

    Founding mécanisme bactérien chez la souris · experiment

    Why it is here: Décrit comment une enzyme d’entérocoques stimule la signalisation NOD2 et améliore la réponse à l’immunothérapie anti-PD-L1.

    Abstract · conclusions of the full text read too

    SagA promotes immunotherapy response The gut microbiome can influence the treatment outcome for cancer patients receiving PD-L1 immunotherapy, but the mechanisms underlying favorable responses are unclear. Griffin et al . found that a particular type of bacteria called enterococci enhance anti–PD-L1 immunotherapy in mice (see the Perspective by Ansaldo and Belkaid). The researchers show that enterococci secrete an enzyme called SagA that breaks down components of the bacterial cell wall. This process results in the release of muramyl peptide fragments, which in turn act as stimulatory molecules to promote signaling of the innate immune sensor protein NOD2 and improved immunotherapy responses. —PNK

  19. [19] Gut microbiome is associated with the clinical response to anti-PD-1 based immunotherapy in hepatobiliary cancers

    Jinzhu Mao, Dongxu Wang, Junyu Long, Yang Xu et al. · 2021 · Journal for ImmunoTherapy of Cancer · cited 293 times · doi:10.1136/jitc-2021-003334

    Founding étude métagénomique longitudinale · observational study

    Why it is here: Cette étude analyse les échantillons fécaux avant et pendant le traitement afin d’associer les profils microbiens aux résultats des anti-PD-1.

    Abstract · conclusions of the full text read too

    BACKGROUND: The gut microbiome is associated with the response to immunotherapy for different cancers. However, the impact of the gut microbiome on hepatobiliary cancers receiving immunotherapy remains unknown. This study aims to investigate the relationship between the gut microbiome and the clinical response to anti-programmed cell death protein 1 (PD-1) immunotherapy in patients with advanced hepatobiliary cancers. METHODS: Patients with unresectable hepatocellular carcinoma or advanced biliary tract cancers who have progressed from first-line chemotherapy (gemcitabine plus cisplatin) were enrolled. Fresh stool samples were collected before and during anti-PD-1 treatment and analyzed with metagenomic sequencing. Significantly differentially enriched taxa and prognosis associated taxa were identified. The Kyoto Encyclopedia of Genes and Genomes database and MetaCyc database were further applied to annotate the differentially enriched taxa to explore the potential mechanism of the gut microbiome influencing cancer immunotherapy. RESULTS: In total, 65 patients with advanced hepatobiliary cancers receiving anti-PD-1 treatment were included in this study. Seventy-four taxa were significantly enriched in the clinical benefit response (CBR) group and 40 taxa were significantly enriched in the non-clinical benefit (NCB) group. Among these taxa, patients with higher abundance of Lachnospiraceae bacterium-GAM79 and Alistipes sp Marseille-P5997, which were significantly enriched in the CBR group, achieved longer progression-free survival (PFS) and overall survival (OS) than patients with lower abundance. Higher abundance of Ruminococcus calidus and Erysipelotichaceae bacterium-GAM147 enriched in the CBR group was also observed in patients with better PFS. In contrast, worse PFS and OS were found in patients with higher abundance of Veillonellaceae, which was significantly enriched in the NCB group. Functional annotation indicated that the taxa enriched in the CBR group were associated with energy metabolism while the taxa enriched in the NCB group were associated with amino acid metabolism, which may modulate the clinical response to immunotherapy in hepatobiliary cancers. In addition, immunotherapy-related adverse events were affected by the gut microbiome diversity and relative abundance. CONCLUSIONS: We demonstrate that the gut microbiome is associated with the clinical response to anti-PD-1 immunotherapy in patients with hepatobiliary cancers. Taxonomic signat

  20. [20] The role of gut microbiome in modulating response to immune checkpoint inhibitor therapy in cancer

    Abdul Rafeh Naqash, Alba J. Kihn-Alarcón, Chara Stavraka, Kathleen Claire Kerrigan et al. · 2021 · Annals of Translational Medicine · cited 50 times · doi:10.21037/atm-20-6427

    Review synthèse des mécanismes et données cliniques · review

    Why it is here: La revue porte directement sur le rôle du microbiome dans la réponse et les toxicités des ICI.

    Abstract · conclusions of the full text read too

    Abstract: Immunotherapy has led to a paradigm shift in the treatment of several cancers. There have been significant efforts to identify biomarkers that can predict response and toxicities related to immune checkpoint inhibitor (ICPI) therapy. Despite these advances, it has been challenging to tease out why a subset of patients benefit more than others or why certain patients experience immune-related adverse events (irAEs). Although the immune-modulating properties of the human gut bacterial ecosystem are yet to be fully elucidated, there has been growing interest in evaluating the role of the gut microbiome in shaping the therapeutic response to cancer immunotherapy. Considerable research efforts are currently directed to utilizing metagenomic and metabolic profiling of stool microbiota in patients on ICPI-based therapies. Dysbiosis or loss of microbial diversity has been associated with a poor treatment response to ICPIs and worse survival outcomes in cancer patients. Emerging data have shown that certain bacterial strains, such as Faecalibacterium that confer sensitivity to ICPI, also have a higher propensity to increase the risk of irAEs. Additionally, the microbiome can modulate the local immune response at the intestinal interface and influence the trafficking of bacterial peptide primed T-cells distally, influencing the toxicity patterns to ICPI. Antibiotic or diet induced alterations in composition of the microbiome can also indirectly alter the production of certain bacterial metabolites such as deoxycholate and short chain fatty acids that can influence the anti-tumor tolerogenesis. Gaining sufficient understanding of the exact mechanisms underpinning the interplay between ICPI induced anti-tumor immunity and the immune modulatory role gut microbiome can be vital in identifying potential avenues of improving outcomes to cancer immunotherapy. In the current review, we have summarized and highlighted the key emerging data supporting the role of gut microbiome in regulating response to ICPIs in cancer.

  21. [21] Cross-cohort gut microbiome associations with immune checkpoint inhibitor response in advanced melanoma

    Karla A. Lee, Andrew Maltez Thomas, Laura A. Bolte, Johannes R. Björk et al. · 2022 · Nature Medicine · cited 497 times · doi:10.1038/s41591-022-01695-5

    analyse métagénomique multicohorte · observational study

    Why it is here: L’étude compare plusieurs cohortes de mélanome et évalue les associations ainsi que la reproductibilité des signatures microbiennes liées à la réponse.

    Abstract

    The composition of the gut microbiome has been associated with clinical responses to immune checkpoint inhibitor (ICI) treatment, but there is limited consensus on the specific microbiome characteristics linked to the clinical benefits of ICIs. We performed shotgun metagenomic sequencing of stool samples collected before ICI initiation from five observational cohorts recruiting ICI-naive patients with advanced cutaneous melanoma (n = 165). Integrating the dataset with 147 metagenomic samples from previously published studies, we found that the gut microbiome has a relevant, but cohort-dependent, association with the response to ICIs. A machine learning analysis confirmed the link between the microbiome and overall response rates (ORRs) and progression-free survival (PFS) with ICIs but also revealed limited reproducibility of microbiome-based signatures across cohorts. Accordingly, a panel of species, including Bifidobacterium pseudocatenulatum, Roseburia spp. and Akkermansia muciniphila, associated with responders was identified, but no single species could be regarded as a fully consistent biomarker across studies. Overall, the role of the human gut microbiome in ICI response appears more complex than previously thought, extending beyond differing microbial species simply present or absent in responders and nonresponders. Future studies should adopt larger sample sizes and take into account the complex interplay of clinical factors with the gut microbiome over the treatment course.

  22. [22] Gut microbiome in modulating immune checkpoint inhibitors

    Xiang Li, Shaoqiang Zhang, Gang Guo, Jing Han et al. · 2022 · EBioMedicine · cited 183 times · doi:10.1016/j.ebiom.2022.104163

    Review revue des données et stratégies · review

    Why it is here: Elle analyse comment le microbiote peut moduler les réponses aux ICI et comment il pourrait être modifié.

    Abstract · conclusions of the full text read too

    Gut microbiome has been increasingly recognized for its influence on a diverse array of human diseases including cancer, and may also influence the outcome of cancer therapies. A prime example is seen in immunotherapy, for which gut microbes determine the therapeutic responses associated with immune checkpoint inhibitors (ICIs) in preclinical models and patient cohorts. This evidence hints that inter-individual variations in the gut microbiota may account for the significant heterogeneity in immunotherapeutic responses to ICIs. Understanding the functional role of gut microbiome in regulating not only mucosal but also systemic immunity and cancer is critical to move forward in this era of precision medicine. What's more, microbiota can be modified via several different strategies that are essential for the efforts in expanding immunotherapy efficacy. This review summarizes latest knowledge about the interactions between microbiome, host immunity and cancer, and strategies to modulate the microbiome with implications to be translated into clinic. FUNDING: This study was supported by National Key R&D Program of China (No. 2020YFA0509200/2020YFA0509203), RGC Theme-based Res Scheme Hong Kong (T21-705/20-N).

  23. [23] Gut microbiota and metabolites associate with outcomes of immune checkpoint inhibitor–treated unresectable hepatocellular carcinoma

    Pei‐Chang Lee, Chi-Jung Wu, Ya‐Wen Hung, Chieh Ju Lee et al. · 2022 · Journal for ImmunoTherapy of Cancer · cited 249 times · doi:10.1136/jitc-2022-004779

    cohortes et profilage métagénomique · observational study

    Why it is here: Compare microbiote et métabolites fécaux selon les résultats cliniques d’une immunothérapie du carcinome hépatocellulaire.

    Abstract · conclusions of the full text read too

    Background Immune checkpoint inhibitors (ICIs) are promising agents for unresectable hepatocellular carcinoma (uHCC), but lack effective biomarker to predict outcomes. The gut microbiome can modulate tumor response to immunotherapy, but its effect on HCC remains unclear. Methods From May 2018 to February 2020, patients receiving ICI treatment for uHCC were prospectively enrolled; their fecal samples were collected before treatment. The fecal microbiota and metabolites were analyzed from 20 patients with radiology-proven objective responses (OR) and 21 randomly selected patients with progressive disease (PD). After March 2020, 33 consecutive Child-Pugh-A patients were recruited as a validation cohort. Additionally, feces from 17 healthy volunteers were collected for comparison of background microbes. Results A significant dissimilarity was observed in fecal bacteria between patients with OR and patients with PD before immunotherapy. Prevotella 9 was enriched in patients with PD, whereas Lachnoclostridium, Lachnospiraceae, and Veillonella were predominant in patients with OR. Ursodeoxycholic acid and ursocholic acid were significantly enriched in the feces of patients with OR and strongly correlated with the abundance of Lachnoclostridium . The coexistence of Lachnoclostridium enrichment and Prevotella 9 depletion significantly predicted better overall survival (OS). In the validation cohort, better progression-free survival (PFS) and OS were noted in patients who had a preferable microbial signature in comparison with counter-group (PFS: 8.8 months vs 1.8 months; OS: not reached vs 6.5 months, both p<0.001). Conclusions Fecal microbiota and bile acids were associated with outcomes of immunotherapy for uHCC. These findings highlight the potential role of gut microbiota and metabolites as biomarkers to predict outcomes of ICI-treated HCC.

  24. [24] Gut microbiota influence immunotherapy responses: mechanisms and therapeutic strategies

    Yuting Lu, Xiangliang Yuan, Miao Wang, Zhihao He et al. · 2022 · Journal of Hematology & Oncology · cited 542 times · doi:10.1186/s13045-022-01273-9

    Review revue mécanistique et thérapeutique · review

    Why it is here: Elle décrit comment microbes et métabolites peuvent modifier l’immunité antitumorale et l’efficacité des ICI.

    Abstract · conclusions of the full text read too

    The gut microbiota have long been recognized to play a key role in human health and disease. Currently, several lines of evidence from preclinical to clinical research have gradually established that the gut microbiota can modulate antitumor immunity and affect the efficacy of cancer immunotherapies, especially immune checkpoint inhibitors (ICIs). Deciphering the underlying mechanisms reveals that the gut microbiota reprogram the immunity of the tumor microenvironment (TME) by engaging innate and/or adaptive immune cells. Notably, one of the primary modes by which the gut microbiota modulate antitumor immunity is by means of metabolites, which are small molecules that could spread from their initial location of the gut and impact local and systemic antitumor immune response to promote ICI efficiency. Mechanistic exploration provides novel insights for developing rational microbiota-based therapeutic strategies by manipulating gut microbiota, such as fecal microbiota transplantation (FMT), probiotics, engineered microbiomes, and specific microbial metabolites, to augment the efficacy of ICI and advance the age utilization of microbiota precision medicine.

  25. [25] Intestinal microbiota signatures of clinical response and immune-related adverse events in melanoma patients treated with anti-PD-1

    John A. McCulloch, Diwakar Davar, Richard Rosario Rodrigues, Jonathan H. Badger et al. · 2022 · Nature Medicine · cited 505 times · doi:10.1038/s41591-022-01698-2

    Review cohorte et méta-analyse microbienne · observational study

    Why it is here: Combine une nouvelle cohorte de mélanome et des jeux de données publiés pour relier des groupes bactériens aux résultats anti-PD-1.

    Abstract

    Ample evidence indicates that the gut microbiome is a tumor-extrinsic factor associated with antitumor response to anti-programmed cell death protein-1 (PD-1) therapy, but inconsistencies exist between published microbial signatures associated with clinical outcomes. To resolve this, we evaluated a new melanoma cohort, along with four published datasets. Time-to-event analysis showed that baseline microbiota composition was optimally associated with clinical outcome at approximately 1 year after initiation of treatment. Meta-analysis and other bioinformatic analyses of the combined data show that bacteria associated with favorable response are confined within the Actinobacteria phylum and the Lachnospiraceae/Ruminococcaceae families of Firmicutes. Conversely, Gram-negative bacteria were associated with an inflammatory host intestinal gene signature, increased blood neutrophil-to-lymphocyte ratio, and unfavorable outcome. Two microbial signatures, enriched for Lachnospiraceae spp. and Streptococcaceae spp., were associated with favorable and unfavorable clinical response, respectively, and with distinct immune-related adverse effects. Despite between-cohort heterogeneity, optimized all-minus-one supervised learning algorithms trained on batch-corrected microbiome data consistently predicted outcomes to programmed cell death protein-1 therapy in all cohorts. Gut microbial communities (microbiotypes) with nonuniform geographical distribution were associated with favorable and unfavorable outcomes, contributing to discrepancies between cohorts. Our findings shed new light on the complex interaction between the gut microbiome and response to cancer immunotherapy, providing a roadmap for future studies. Integrated analysis of microbiome and host cell transcriptional data on clinically annotated cohorts of patients with melanoma who were treated with anti-programmed cell death protein-1, uncovers new associations of streptococcus species with immune-related adverse effects and finds consistent microbiome associations with clinical outcomes.

  26. [26] Critical role of the gut microbiota in immune responses and cancer immunotherapy

    Zehua Li, Weixi Xiong, Liang Wei Zhu, Jinyu Wang et al. · 2024 · Journal of Hematology & Oncology · cited 198 times · doi:10.1186/s13045-024-01541-w

    Recent Review synthèse immunologique et interventions microbiennes · review

    Why it is here: La revue examine le crosstalk entre microbiote, immunité et immunothérapie, ainsi que des stratégies pour améliorer l’efficacité.

    Abstract · conclusions of the full text read too

    The gut microbiota plays a critical role in the progression of human diseases, especially cancer. In recent decades, there has been accumulating evidence of the connections between the gut microbiota and cancer immunotherapy. Therefore, understanding the functional role of the gut microbiota in regulating immune responses to cancer immunotherapy is crucial for developing precision medicine. In this review, we extract insights from state-of-the-art research to decipher the complicated crosstalk among the gut microbiota, the systemic immune system, and immunotherapy in the context of cancer. Additionally, as the gut microbiota can account for immune-related adverse events, we discuss potential interventions to minimize these adverse effects and discuss the clinical application of five microbiota-targeted strategies that precisely increase the efficacy of cancer immunotherapy. Finally, as the gut microbiota holds promising potential as a target for precision cancer immunotherapeutics, we summarize current challenges and provide a general outlook on future directions in this field.

  27. [27] Custom scoring based on ecological topology of gut microbiota associated with cancer immunotherapy outcome

    Lisa Derosa, Valerio Iebba, Carolina Alves Costa Silva, Gianmarco Piccinno et al. · 2024 · Cell · cited 225 times · doi:10.1016/j.cell.2024.05.029

    Recent réseaux microbiens et score prédictif · method

    Why it is here: Construit et valide un score fondé sur les interactions entre espèces pour prédire les résultats des inhibiteurs dans plusieurs cohortes.

    Abstract

    The gut microbiota influences the clinical responses of cancer patients to immunecheckpoint inhibitors (ICIs). However, there is no consensus definition of detrimental dysbiosis. Based on metagenomics (MG) sequencing of 245 non-small cell lung cancer (NSCLC) patient feces, we constructed species-level co-abundance networks that were clustered into species-interacting groups (SIGs) correlating with overall survival. Thirty-seven and forty-five MG species (MGSs) were associated with resistance (SIG1) and response (SIG2) to ICIs, respectively. When combined with the quantification of Akkermansia species, this procedure allowed a person-based calculation of a topological score (TOPOSCORE) that was validated in an additional 254 NSCLC patients and in 216 genitourinary cancer patients. Finally, this TOPOSCORE was translated into a 21-bacterial probe set-based qPCR scoring that was validated in a prospective cohort of NSCLC patients as well as in colorectal and melanoma patients. This approach could represent a dynamic diagnosis tool for intestinal dysbiosis to guide personalized microbiota-centered interventions.

  28. [28] Gut microbiota reshapes cancer immunotherapy efficacy: Mechanisms and therapeutic strategies

    Jindong Xie, Manqing Liu, Xinpei Deng, Yuhui Tang et al. · 2024 · iMeta · cited 107 times · doi:10.1002/imt2.156

    Recent Review revue des mécanismes et interventions · review

    Why it is here: La revue relie composition et métabolites microbiens aux réponses et toxicités des immunothérapies, dont les ICI.

    Abstract · conclusions of the full text read too

    Gut microbiota is essential for maintaining local and systemic immune homeostasis in the presence of bacterial challenges. It has been demonstrated that microbiota play contrasting roles in cancer development as well as anticancer immunity. Cancer immunotherapy, a novel anticancer therapy that relies on the stimulation of host immunity, has suffered from a low responding rate and incidence of severe immune-related adverse events (irAEs). Previous studies have demonstrated that the diversity and composition of gut microbiota were associated with the heterogeneity of therapeutic effects. Therefore, alteration in microbiota taxa can lead to improved clinical outcomes in immunotherapy. In this review, we determine whether microbiota composition or microbiota-derived metabolites are linked to responses to immunotherapy and irAEs. Moreover, we discuss various approaches to improve immunotherapy efficacy or reduce toxicities by modulating microbiota composition.

  29. [29] Insights into the Relationship Between the Gut Microbiome and Immune Checkpoint Inhibitors in Solid Tumors

    Soňa Čierniková, Aneta Ševčíková, Mária Novisedláková, Michal Mego · 2024 · Cancers · cited 23 times · doi:10.3390/cancers16244271

    Recent Review revue des réponses et toxicités · review

    Why it is here: Elle relie composition microbienne, réponse antitumorale et toxicités, et présente des interventions de modulation du microbiote.

    Abstract · conclusions of the full text read too

    Immunotherapy with immune checkpoint inhibitors represents a revolutionary approach to the treatment of solid tumors, including malignant melanoma, lung cancer, and gastrointestinal malignancies. Anti-CTLA-4 and anti-PD-1/PDL-1 therapies provide prolonged survival for cancer patients, but their efficacy and safety are highly variable. This review focuses on the crucial role of the gut microbiome in modulating the efficacy and toxicity of immune checkpoint blockade. Studies suggest that the composition of the gut microbiome may influence the response to immunotherapy, with specific bacterial strains able to promote an anti-tumor immune response. On the other hand, dysbiosis may increase the risk of adverse effects, such as immune-mediated colitis. Interventions aimed at modulating the microbiome, including the use of probiotics, prebiotics, fecal microbial transplantation, or dietary modifications, represent promising strategies to increase treatment efficacy and reduce toxicity. The combination of immunotherapy with the microbiome-based strategy opens up new possibilities for personalized treatment. In addition, factors such as physical activity and nutritional supplementation may indirectly influence the gut ecosystem and consequently improve treatment outcomes in refractory patients, leading to enhanced patient responses and prolonged survival.

  30. [30] Longitudinal gut microbiome changes in immune checkpoint blockade-treated advanced melanoma

    Johannes R. Björk, Laura A. Bolte, Andrew Maltez Thomas, Karla A. Lee et al. · 2024 · Nature Medicine · cited 175 times · doi:10.1038/s41591-024-02803-3

    Recent profilage longitudinal du mélanome · observational study

    Why it is here: Suit les changements microbiens pendant le traitement et les relie à la durée de survie sans progression sous blocage immunitaire.

    Abstract

    Abstract Multiple clinical trials targeting the gut microbiome are being conducted to optimize treatment outcomes for immune checkpoint blockade (ICB). To improve the success of these interventions, understanding gut microbiome changes during ICB is urgently needed. Here through longitudinal microbiome profiling of 175 patients treated with ICB for advanced melanoma, we show that several microbial species-level genome bins (SGBs) and pathways exhibit distinct patterns from baseline in patients achieving progression-free survival (PFS) of 12 months or longer (PFS ≥12) versus patients with PFS shorter than 12 months (PFS <12). Out of 99 SGBs that could discriminate between these two groups, 20 were differentially abundant only at baseline, while 42 were differentially abundant only after treatment initiation. We identify five and four SGBs that had consistently higher abundances in patients with PFS ≥12 and <12 months, respectively. Constructing a log ratio of these SGBs, we find an association with overall survival. Finally, we find different microbial dynamics in different clinical contexts including the type of ICB regimen, development of immune-related adverse events and concomitant medication use. Insights into the longitudinal dynamics of the gut microbiome in association with host factors and treatment regimens will be critical for guiding rational microbiome-targeted therapies aimed at enhancing ICB efficacy.