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Cited by 689Cancer Immunotherapy and BiomarkersGut microbiota and healthFerroptosis and cancer prognosis

Intestinal Akkermansia muciniphila predicts clinical response to PD-1 blockade in patients with advanced non-small-cell lung cancer

Open access
Derosa, Lisa, Routy, Bertrand, Thomas, Andrew Maltez, Iebba, Valerio, Zalcman, Gerard, Friard, Sylvie, Mazieres, Julien, Audigier-Valette, Clarisse +35 more·2022·Nature Medicine
DOI 10.1038/s41591-021-01655-5PMC PMC9330544
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Abstract

Aside from PD-L1 expression, biomarkers of response to immune checkpoint inhibitors (ICIs) in non-small-cell lung cancer (NSCLC) are needed. In a previous retrospective analysis, we documented that fecal Akkermansia muciniphila (Akk) was associated with clinical benefit of ICI in patients with NSCLC or kidney cancer. In the current study, we performed shotgun-metagenomics-based microbiome profiling in a large cohort of patients with advanced NSCLC (n = 338) treated with first- or second-line ICIs to prospectively validate the predictive value of fecal Akk. Baseline stool Akk was associated with increased objective response rates and overall survival in multivariate analyses, independent of PD-L1 expression, antibiotics, and performance status. Intestinal Akk was accompanied by a richer commensalism, including Eubacterium hallii and Bifidobacterium adolescentis, and a more inflamed tumor microenvironment in a subset of patients. However, antibiotic use (20% of cases) coincided with a relative dominance of Akk above 4.8% accompanied with the genus Clostridium, both associated with resistance to ICI. Our study shows significant differences in relative abundance of Akk that may represent potential biomarkers to refine patient stratification in future studies.

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Crossref · 10.1038/s41591-021-01655-5

Cites

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Claims the paper makes

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  • Findingown data

    Among first-line immunotherapy-alone patients, 59% of Akk-positive patients were alive at 12 months versus 35% of Akk-negative patients (p=0.04).

    “For the 1L IO patients, 59% of Akk + patients were still alive after 12 months (OS ≥ 12) while only 35% of Akk -individuals were long term survivors (Figure 1E, p=0.04).”
    Quote in the paperSubstantial claim
  • Findingown data

    In preclinical avatar mouse experiments, resistance to anti-PD-1 therapy was associated with absence of detectable Akk in fecal microbiota transplant experiments.

    “As observed in our clinical cohort, resistance to therapy in mice was associated with the absence of detectable Akk in the FMT experiments (Extended Figure 2C-D).”
    Quote in the paperSubstantial claim
  • Findingown data

    In the first-line immunotherapy-alone subgroup of 86 patients, objective response rates were 41% in Akk-positive versus 19% in Akk-negative patients (p=0.016).

    “When considering the subgroup of patients who received immunotherapy alone as front-line treatment (1L IO, n=86), ORR were 41% and 19% in the Akk + versus Akk -respectively (Figure 1B, p=0.016).”
    Quote in the paperSubstantial claim
  • Findingown data

    Kernel density estimation showed that patients with Akk high, defined as relative abundance above the 75th percentile (4.656%), clustered within the overall survival less than 12 months group (p=0.005).

    “Using a Kernel density estimation of the relative abundance of Akk positionning patients with OS ≥ 12 or OS < 12, we noticed that patients harboring Akk high , at a relative abundance > 75 th percentile (4.656%), did cluster within the OS < 12 months (Figure 2B-C left panel, p=0.005).”
    Quote in the paperSubstantial claim
  • Findingown data

    Shannon diversity was significantly higher in Akk low than in Akk-negative or Akk high specimens (p=0.00003).

    “Moreover, we found a significant increase in Shannon diversity in Akk low compared to Akk -or Akk high specimens (Extended Figure 4A, p=0.00003)”
    Quote in the paperNot a substantial claim
  • May combine two claims. 33
  • Classified as probably not a substantial claim. 20

  • May combine two claims.

    Findingown data

    Using shotgun metagenomic sequencing and MetaPhlAn profiling, Akk was detectable in 131 of 338 patients (39%) and absent in 207 (61%).

    “Using shotgun metagenomic sequencing, we determined that Akk was detectable in 131 (39%) and absent in 207 (61%) patients using MetaPhlAn profiling expanded to identify the main Akk species-level genome bin (SGB9226 spp 35 , M&M Table 1).”
    Quote in the paperSubstantial claim

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

    Findingown data

    There was a non-statistically significant trend toward older age in the Akk-positive group (66 versus 64 years, p=0.08).

    “However, there was a non-statistically significant trend for older age in theAkk + group (66 years versus 64 years, p=0.08).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Akk high levels and antibiotic exposure were standalone variables associated with shorter overall survival in NSCLC patients treated with immune checkpoint inhibitors.

    “Akk high levels as well as ATB exposure were considered standalone variables associated with shorter OS in NSCLC patients treated with ICI.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Sixty-nine patients (20%) received antibiotics within 60 days before immune checkpoint inhibitor initiation, with similar frequencies and regimens in Akk-positive and Akk-negative groups.

    “A total of 69 patients (20%) received antibiotics (ATB) 60 days prior to ICI initiation, with similar frequencies (p=0.68) and regimen in Akk + and Akk -groups (Table S1A).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Within the Akk-positive group, overall microbial composition differed between patients with overall survival at least 12 months and those with less than 12 months, but this difference was not observed in Akk-negative patients (p=0.009 versus p=0.07).

    “Furthermore, within the Akk + group, we found significant differences in the overall microbial composition between patients with OS ≥ 12 versus OS < 12 months, but this difference was not observed in Akk -patients (Figure 2A, p=0.009 versus p=0.07).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    LEfSe analysis found Ruminococcaceae, Lachnospiraceae, and Alistipes species enriched in Akk-positive stools.

    “we found Ruminococcacae (Ruminococcus bromii, R. bicirculans, R. lactaris), Lachnospiraceae (Eubacterium siraeum, E. eligens) family members and Alistipes spp.(A.inops, A. finegoldii, A. indistinctus, A. shahii) to be enriched in Akk + stools as previously reported, 41”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [41] Benevides, L. et al. New insights into the diversity of the genus Faecalibacterium. Front. Microbiol. 8, 1790 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    In the whole cohort, median overall survival was 18.8 months in Akk-positive patients versus 15.4 months in Akk-negative patients (HR=0.72; 95% CI 0.73-1.62; p=0.03).

    “Of note, for the whole cohort of patients (irrespective of the line of treatment), the median overall survival (mOS) was 18.8 months for the Akk + group compared to 15.4 months in the Akk - group (HR=0.72;(95% CI :0.73-1.62);p=0.03, Figure 1C, Table S1A).”
    Quote in the paperSubstantial claim

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

    Findingcitation

    The same conclusions were reached when using the MetaOMineR pipeline.

    “We draw the same conclusions when using the MetaOMineR pipeline 36 (Extended Figure 2A-B”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [36] Meng, X. et al. Immune microenvironment differences between squamous and non-squamous non-small-cell lung cancer and their influence on the prognosis. Clin. Lung Cancer 20, 48–58 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    Partial response, stable disease, and progressive disease rates were 28%, 28%, and 44% in the Akk-positive group versus 18%, 31%, and 50% in the Akk-negative group.

    “Partial responses (PR), stable disease (SD) and progressive disease (PD) rates were 28%, 28% and 44%, respectively, for the Akk + group versus 18%, 31% and 50% for the Akk -group.”
    Quote in the paperSubstantial claim

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

    Findingown data

    Beta-lactams were the most commonly prescribed antibiotic class in both groups (80% in Akk-positive versus 64% in Akk-negative, p=0.33).

    “Among ATB classes, beta-lactams were the most commonly prescribed in both groups (Table S1B, 80% in Akk + versus 64% in Akk -, p=0.33).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Overall microbial community composition showed clear separation between Akk-negative and Akk low patients and between Akk low and Akk high patients (p=0.0001 and p=0.0003, respectively).

    “with the overall microbial community showing clear separation between Akk -versus Akk low as well as between Akk low versus Akk high patients (Extended Figure 4B-C, p=0.0001 and p=0.0003, respectively).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Antibiotic exposure was associated with shorter overall survival in univariable analysis (p=0.009) and in multivariable analysis (p=0.088).

    “In addition, ATB exposure was associated with shorter OS (in univariable analysis, p=0.009 (Table S4B, Table S5), and multivariate analysis, p=0.088 (Table 1, Table S5).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Fecal microbiota transplantation from Akk-positive stools conferred sensitivity to anti-PD-1 antibody, whereas FMT from Akk-negative stools conferred resistance, compared with SPF eubiotic mice without FMT.

    “FMT could confer sensitivity (when stools were Akk + ) or resistance (when stools were Akk neg) to anti-PD-1 Ab, when compared with animals in eubiosis reared in SPF conditions (without FMT).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In antibiotic-free subjects, Akk high patients had reduced benefit from immune checkpoint inhibitors compared with Akk low individuals but not worse than the Akk-negative subgroup.

    “In ATB-free subjects, Akk high patients exhibited a reduced benefit to ICI compared with Akk low individuals but not worse than the Akk neg subgroup (Figure 2G left panel).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Apart from Akk, few bacteria, including Eubacterium hallii, Bifidobacterium adolescentis, Parasutterella excrementihominis, Intestinimonas butyriciproducens, and C. innocuum, were associated with prolonged or reduced survival after immune checkpoint inhibitor therapy with a linear dose response, unlike Akk.

    “Apart from Akk, very few bacteria (except Eubacterium hallii, Bifidobacterium adolescentis, Parasutterella excrementihominis, Intestinimonas butyriciproducens, or C. innocuum already described to mediate immunomodulatory functions [43][44][45] were also associated with prolonged (Figure 3B, Figure 3D) or reduced survival following ICI therapy (Figure 3F, Table S6)”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [43] Elkrief, A., Derosa, L., Kroemer, G., Zitvogel, L. & Routy, B. The negative impact of antibiotics on outcomes in cancer patients treated with immunotherapy: a new independent prognostic factor? Ann. Oncol. 30, 1572–1579 (2019). source

      Not checked in the free run.

    • cites [44] Seo, S. W., Kim, D., Szubin, R. & Palsson, B. O. Genome-wide reconstruction of OxyR and SoxRS Transcriptional regulatory networks under oxidative stress in Escherichia coli K-12 MG1655. Cell Rep. 12, 1289–1299 (2015). source

      Not checked in the free run.

    • cites [45] Atarashi, K. et al. Induction of colonic regulatory T cells by indigenous Clostridium species. Science 331, 337–341 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    Statistical analyses identified 16 bacterial species, of which 14 were positively and 2 negatively associated with Akk fecal prevalence independently of age, gender, BMI, and lines of therapy.

    “to compare taxonomic compositional variations between Akk + versus Akk -stools in order to identify 16 bacterial species, among which 14 were positively and 2 were negatively associated with Akk fecal prevalence independently of other confounding factors such as age, gender, BMI, lines of therapy”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The study also observed a greater than 10% objective response rate increase between Akk-negative and Akk-positive patients (from 19% to 41%) with a median overall survival advantage in first-line NSCLC patients.

    “Moreover, we also observed a > 10% ORR increase between Akk -and Akk + (from 19% to 41% ORR, Figure 1B) with a mOS advantage in 1L NSCLC patients (Figure 1E).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Akk was associated not only with increased alpha diversity but also with a distinct bacterial community associated with health or immunogenic status, represented by Ruminococcaceae and Lachnospiraceae family members.

    “we report that Akk was associated not only with increased alpha diversity but also with a distinct bacterial community associated with a health or immunogenic status represented by Ruminococcacae (Faecalibacterium prausnitzii, R. lactaris) and Lachnospiraceae (Dorea formicigenerans & D. longicatena, Eubacterium rectale & E. hallii, Roseburia faecis & R. intestinalis) family members”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Akkp2261 modulates the murine microbiome composition and rescues responsiveness to PD-1 blockade.

    “Akkp2261 modulated the murine microbiome composition, rescuing responsiveness to PD-1 blockade.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Responder mice had a relative overrepresentation of metagenomic species that are annotated in Figure 3A as present in humans with Akk+ stools, specifically Intestinimonas butyriciproducens and Parasuterrella excrementihominis, compared with non-responder mice, which tended to be enriched in Bacteroides spp.

    “R mice harbored a relative overrepresentation of metagenomics species annotated in Figure3Ain humans harboring Akk + stools namely Intestinimonas butyriciproducens, Parasuterrella excrementihominis compared with NR mice, that in contrast, tended to be enriched in Bacteroides spp (Extended Figure6Eright panel).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The composition of the gut microbiota influences peripheral immune tone and the effectiveness of immune checkpoint inhibitors in cancer patients.

    “Recent lines of evidence point to the biological significance of the composition of the gut microbiota in influencing peripheral immune tonus and effectiveness of ICI in patients with cancer 17 .”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [17] Routy, B. et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science 359, 91–97 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A diverse microbiota and the presence of specific bacteria such as Akkermansia muciniphila, Ruminococcus, or Bifidobacterium are associated with improved clinical response to immune checkpoint inhibitors and increased systemic immune tone.

    “A diverse microbiota and the presence of specific bacteria such as Akkermansia muciniphila, Ruminococcus or Bifidobacterium genera were associated with improved clinical response to ICI, correlating with increased systemic immune tonus 18,20,25 .”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [18] Vétizou, M. et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science 350, 1079–1084 (2015). source

      Not checked in the free run.

    • cites [20] Derosa, L. et al. Negative association of antibiotics on clinical activity of immune checkpoint inhibitors in patients with advanced renal cell and non-small-cell lung cancer. Ann. Oncol. 29, 1437–1444 (2018). source

      Not checked in the free run.

    • cites [25] Santoro, A. et al. Gut microbiota changes in the extreme decades of human life: a focus on centenarians. Cell. Mol. Life Sci. 75, 129–148 (2018). source

      Not checked in the free run.

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

    Premisecitation

    Immune checkpoint inhibitors targeting PD-1/PD-L1 have changed the treatment landscape for advanced non-small-cell lung cancer.

    “The development of immune checkpoint inhibitors (ICI) targeting the PD-1/PD-L1 interaction has transformed the therapeutic landscape of patients with advanced non-small cell lung cancer (NSCLC) [1][2][3][4][5][6] .”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [1] Herbst, R. S. et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet 387, 1540–1550 (2016). source

      Not checked in the free run.

    • cites [2] Brahmer, J. et al. Nivolumab versus docetaxel in advanced squamous-cell non–small-cell lung cancer. N. Engl. J. Med. 373, 123–135 (2015). source

      Not checked in the free run.

    • cites [3] Borghaei, H. et al. Nivolumab versus docetaxel in advanced nonsquamous non–small-cell lung cancer. N. Engl. J. Med. 373, 1627–1639 (2015). source

      Not checked in the free run.

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

    Premisecitation

    Most NSCLC patients develop primary or secondary resistance, or occasionally hyper-progression.

    “Most patients with NSCLC patients develop primary or secondary resistance, or occasional rapid acceleration of the disease called “hyper-progression” 9 .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [9] Riaz, N. et al. Tumor and microenvironment evolution during immunotherapy with nivolumab. Cell 171, 934–949.e16 (2017). source

      Not checked in the free run.

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

    Premisecitation

    In previously treated advanced NSCLC, PD-1/PD-L1 blockade improved overall survival compared with standard chemotherapy.

    “Landmark trials performed on previously treated patients with advanced NSCLC demonstrated superior overall survival (OS) with PD-1/PD-L1 blockade compared to standard chemotherapy [1][2][3] .”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [1] Herbst, R. S. et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet 387, 1540–1550 (2016). source

      Not checked in the free run.

    • cites [2] Brahmer, J. et al. Nivolumab versus docetaxel in advanced squamous-cell non–small-cell lung cancer. N. Engl. J. Med. 373, 123–135 (2015). source

      Not checked in the free run.

    • cites [3] Borghaei, H. et al. Nivolumab versus docetaxel in advanced nonsquamous non–small-cell lung cancer. N. Engl. J. Med. 373, 1627–1639 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Normal levels of Akk in the gut, Akk low, may be a surrogate of host intestinal fitness.

    “The presence of “normal levels” of Akk in the gut (Akk low ) may be considered as a surrogate of host intestinal fitness.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    The proportional hazards assumption was questionable only for antibiotics (Schoenfeld residuals trend test p=0.016), but no statistically significant interaction with time was identified.

    “The proportionality hazard assumption was questionable only for the ATB (Schoenfeld residuals trend test p=0.016),but no statistically significant interaction with time could be identified.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    In this independent prospective study of 338 advanced NSCLC patients, the presence of Akk is associated with higher objective response rates and longer overall survival in patients receiving immune checkpoint inhibitors, validated in humans with two metagenomic pipelines and in mice.

    “Therefore, in this second independent and prospective study on 338 advanced NSCLC patients, we validated in humans using two different metagenomics pipelines as well as in mice that the presence of Akk is associated with higher ORR and longer OS in patients with NSCLC receiving ICI.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    In patients treated with abiraterone acetate for metastatic castration-resistant prostate cancer, intestinal Akk correlated with therapeutic responses.

    “In patients treated with Abiraterone acetate, an inhibitor of androgen biosynthesis approved to treat metastatic castration-resistant prostate cancer, intestinal Akk also correlated with therapeutic responses 27 .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [27] Blacher, E. et al. Potential roles of gut microbiome and metabolites in modulating ALS in mice. Nature 572, 474–480 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    The intestinal residence of Akk was a proxy of gut ecosystem richness, as shown by the association of Akk at a relative abundance within the 77th percentile (Akk low <4.799%) with stool alpha diversity.

    “The intestinal residence of Akk was a proxy of richness of the gut ecosystem, as shown by the association of Akk at a relative abundance within the 77 th percentile (Akk low < 4.799%), with stool alpha diversity (Shannon diversity index).”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    The study failed to investigate the functional and clinical relevance of rare Akkermansia species other than SGB9226, which was monitored using MetaPhlAn 3 with a custom marker database.

    “Moreover, this study failed to investigate the functional and clinical relevance of more rare Akkermansia spp.58 different from the SGB9226 monitored in this study using MetaPhlAn 3 pipeline with a custom marker database (see Methods).”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    The proportional hazards assumption was checked by testing Schoenfeld residuals.

    “The proportionality hazard assumption was checked testing the trend of the Schoenfeld residuals with the cox.zphR function.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    The study did not evaluate the predictive value of Akk in first-line chemo-immunotherapy combinations; it only considered first-line immunotherapy in patients with PD-L1 >50% tumor expression.

    “First, it did not evaluate the predictive value of Akk in 1L chemo-immunotherapy combinations (only considering 1L IO presenting with PD-L1 >50% tumor expression).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Antibiotic exposure is a negative predictor of survival to immune checkpoint inhibitors and is associated with overabundance of Akk and relative dominance of Clostridium species.

    “Altogether, these results demonstrate that ATB exposure is a negative predictor of survival to ICI, associated with overabundance of Akk (Akk high ) and the relative dominance of Clostridium spp (C.bolteae, Lachnoclostridium).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    The study linked gut microbiota composition to the tumor microenvironmental landscape, highlighting increased transcription of adaptive immunity gene products and the IFN fingerprint.

    “Moreover, our study linked the gut microbiota composition to the tumor microenvironmental landscape, highlighting increased transcription of gene products of the adaptive immunity and the IFN fingerprint.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    These results expand previous observations in smaller NSCLC cohorts and provide evidence that gut microbiome diversity and composition, specifically the relative abundance of Akk, offer relevant information to predict survival of NSCLC patients amenable to immune checkpoint inhibitors.

    “These results expand on previous observations that have been made in smaller cohorts of patients with NSCLC 18,41 and provide evidence that gut microbiome diversity and composition, specifically the relative abundance of Akk, offer relevant information to predict survival of patients with NSCLC amenable to ICI.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [18] Vétizou, M. et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science 350, 1079–1084 (2015). source

      Not checked in the free run.

    • cites [41] Benevides, L. et al. New insights into the diversity of the genus Faecalibacterium. Front. Microbiol. 8, 1790 (2017). source

      Not checked in the free run.

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

    Study design and conductnone given

    Reported p-values were adjusted using Benjamini-Hochberg two-stage false discovery rate at 10%.

    “All reported p-values underwent Benjamini-Hochberg two-stages False Discovery Rate (FDR) at 10%.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    These findings reconcile results across several works, geographical distributions, and sequencing technologies, since Faecalibacterium, Ruminococcus, and Bifidobacterium were previously reported to be enriched in North-American, Japanese, and South Korean patients with melanoma and NSCLC and to have favorable outcome.

    “These findings reconcile the results across several works, geographical distributions and sequencing technologies since Faecalibacterium, Ruminococcus and Bifidobacterium were previously reported to be enriched in North-American, Japanese and South Korean patients with melanoma and NSCLC cancers and have favorable outcome 17,20,41,44 .”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [17] Routy, B. et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science 359, 91–97 (2018). source

      Not checked in the free run.

    • cites [20] Derosa, L. et al. Negative association of antibiotics on clinical activity of immune checkpoint inhibitors in patients with advanced renal cell and non-small-cell lung cancer. Ann. Oncol. 29, 1437–1444 (2018). source

      Not checked in the free run.

    • cites [41] Benevides, L. et al. New insights into the diversity of the genus Faecalibacterium. Front. Microbiol. 8, 1790 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Overabundance of Akk above 4.799 was associated with shorter overall survival than normal relative abundance below 4.799, possibly reflecting an underlying pathophysiological disorder of the intestinal barrier in advanced cancer patients.

    “Aside from ATB use, overabundance of Akk > 4.799 (Akk high ) was associated with a shorter overall survival than “normal” relative abundance of Akk < 4.799, possibly reflecting an underlying pathophysiological disorder of the intestinal barrier in these advanced cancer patients.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    Differential abundance analyses included covariates for age, sex, BMI, cohort, and sequencing batch.

    “We added further support of differentially abundant species using two different multivariate differential abundance methods; ANCOM-BC 66 and MaAsLin2 67 , that included covariates such as age, sex, BMI, cohort and sequencing batch.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [66]

      Not checked in the free run.

    • cites [67]

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    The study was powered at 80% with a two-sided alpha of 5% to detect an ORR increase from 10% in Akk- to 20% in Akk+.

    “Given the superiority hypothesis, power was set at 80% with a two-sided alpha level of 5%, using EAST® program.”
    Quote in the paperSubstantial claim

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

    Study design and conductown data

    Adjustments for multiple comparisons were not made in the analysis of Akkp2261-related tumor reduction.

    “Adjustments for multiple comparisons were not made.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    A recent preclinical study indicates that anticancer effects of recombinant interleukin-2 could be improved by Akk in a Toll-like receptor-2 dependent fashion.

    “A recent preclinical study indicates that the anticancer effects of recombinant interleukin-2 could be improved by Akk in a Toll-like receptor-2 dependent fashion 55 .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [55] Eisenhauer, E. A. et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur. J. Cancer 45, 228–247 (2009).

      Not checked in the free run.

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

    Study design and conductown data

    In the analysis of Akk association with objective response rate, chi-square test P-values were two-sided and no adjustments were made for multiple comparisons.

    “Chi-square test P-values are two-sided, with no adjustments made for multiple comparisons (A).”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    For the comparison of Akk status, P-values were one-sided with no adjustment.

    “P-values are one-sided with no adjustment (B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Avatar mice that received fecal material from Akk-negative humans exhibited tumor resistance to PD-1 blockade, but this resistance was rescued by Akkp2261 when Akkp2261 shifted the microbiome toward the favorable Akk-associated collateral ecosystem.

    “Altogether, avatar mice transferred with Akk -human fecal material exhibited a phenotype of tumor resistance to PD-1 blockade but were rescued by Akkp2261 when Akkp2261 could shift the microbiome towards the favorable Akk associated collateral ecosystem.”
    Quote in the paperSubstantial claim

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

    Study design and conductreasoning

    At least 292 patients, with 146 in each Akk group, were determined necessary to confirm the primary objective.

    “Hence, we determined that at least 292 patients-with equal distribution of 146 patients in both Akk + and Akk -groups -would be necessary to confirm our primary objective.59 .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [59] Fumet, J.-D. et al. Prognostic and predictive role of CD8 and PD-L1 determination in lung tumor tissue of patients under anti-PD-1 therapy. Br. J. Cancer 119, 950–960 (2018). source

      Not checked in the free run.

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

    Study design and conductnone given

    The 60 patients with NSCLC already described in a previous report were excluded from the principal analysis.

    “Of note, the 60 patients with NSCLC already described in our previous report 18 were excluded from the principal analysis.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [18] Vétizou, M. et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science 350, 1079–1084 (2015). source

      Not checked in the free run.

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

    Premisecitation

    In patients, food supplementation with Akk is safe and reduces insulin resistance and dyslipidemia in pre-diabetes.

    “In patients, food supplementation with Akk is safe and reduces insulinoresistance and dyslipidemia in the context of pre-diabetes 56,57 .”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [56] Li, J. et al. An integrated catalog of reference genes in the human gut microbiome. Nat. Biotechnol. 32, 834–841 (2014). source

      Not checked in the free run.

    • cites [57] Nielsen, H. B. et al. Identification and assembly of genomes and genetic elements in complex metagenomic samples without using reference genomes. Nat. Biotechnol. 32, 822–828 (2014). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductown data

    Multivariate analyses used Cox regression models to estimate hazard ratios and 95% confidence intervals for overall survival, adjusting for other clinicopathologic features.

    “Multivariate analyses were performed using Cox regression models to determine HRs and 95% confidence intervals (CIs) for OS adjusting for other clinicopathologic features.”
    Quote in the paperSubstantial claim
50 of 50

  • The paper relies on this without support.

    Shotgun metagenomics quantifies Akk relative abundance more precisely than 16S rRNA sequencing.

    “It may be of utmost importance to risk-stratified I-O patients based on shot-gun metagenomics (rather than by 16S rRNA) sequencing to precisely quantify the relative abundance of Akk in addition to ATB use, and PD-L1 expression in prospective trials including NSCLC patients and designed to discover optimal biomarkers.”

  • The paper relies on this without support.

    Preclinical mouse results with Akk supplementation are predictive of clinical benefit in human NSCLC patients.

    “Altogether, we surmise that therapeutic supplementation with a lyophilized encapsulated Akkp2261 would benefit the subgroups of patients not exposed to ATB, and devoid of endogenous Akk.”
2 of 2

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Intestinal dysbiosis, broadly defined as an imbalance in the composition or function of the gut microbiota, is a significant contributor to resistance against immune checkpoint inhibitor (ICI) therapies.

    “Intestinal dysbiosis, broadly defined as an imbalance in the composition or function of the gut microbiota, is a significant contributor to resistance against immune checkpoint inhibitor (ICI) therapies.1–16,”

    From Gut dysbiosis in oncology: a risk factor for immunoresistance (2026) · cites this paper as [3]

  • Our group has identified at least two distinct forms of dysbiosis, defined by either the close-to-complete absence or overabundance of Akkermansia muciniphila.

    “our group has identified at least two distinct forms of dysbiosis, defined by either the close-to-complete absence or overabundance of Akkermansia muciniphila.3”

    From Gut dysbiosis in oncology: a risk factor for immunoresistance (2026) · cites this paper as [3]

  • A. muciniphila B is a distinct species from A. muciniphila.

    “It should be noted that A. muciniphila B is a distinct species from A. muciniphila; although the latter was positively implicated in anti-PD-1 efficacy in NSCLC 13 (also positive in our study but not within the top 22 strains), recent analyses have revealed that it is phylogenetically and phenotypically distinct from A. muciniphila B (known as Akkermansia SGB9228 by MetaPhlAn4 taxonomy) 21 .”

    From A gut microbial signature for combination immune checkpoint blockade across cancer types (2024) · cites this paper as [13]

  • The trichotomic distribution of Akkermansia spp. (absence, below 4.8%, and at or above 4.8%) enables accurate prediction of clinical benefit in advanced NSCLC receiving first- or second-line anti-PD-(L)1, independently of other clinical prognostic factors.

    “This trichotomic distribution of Akkermansia spp. (absence, <4.8% and ≥4.8%) enables an accurate prediction of clinical benefit in patients with advanced-stage NSCLC receiving first-line or second-line anti-PD-(L)1 antibodies, independently of other clinical prognostic factors41,42.”

    From Gut OncoMicrobiome Signatures (GOMS) as next-generation biomarkers for cancer immunotherapy (2023) · cites this paper as [41]

  • Enrichment of SGB9226 or SGB9228 beyond 4.8% (in 9% of patients), typically caused by antibiotic resistance and coinciding with dominance of immunosuppressive Enterocloster and Clostridium, predicted resistance to anti-PD-(L)1.

    “An enrichment of SGB9226 (or SGB9228, another species of Akkermansia) beyond the 4.8% threshold (in 9% of patients), which is typically caused by antibiotic resistance and thus coincides with a dominance of the immunosuppressive Enterocloster genus and Clostridium species23,25, predicted resistance to anti-PD-(L)1 antibodies41.”

    From Gut OncoMicrobiome Signatures (GOMS) as next-generation biomarkers for cancer immunotherapy (2023) · cites this paper as [41]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Reported hazard ratio falls outside its confidence interval

    Major

    The reported hazard ratio is 0.72, but its stated 95% confidence interval starts at 0.73. A confidence interval for this estimate cannot exclude the estimate itself.

1 of 1

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Authors
Derosa, L., Routy, B., Thomas, A. M., Iebba, V., Zalcman, G., Friard, S., Mazieres, J., Audigier-Valette, C., Moro-Sibilot, D., Goldwasser, F., Silva, C. A. C., Terrisse, S., Bonvalet, M., Scherpereel, A., Pegliasco, H., Richard, C., Ghiringhelli, F., Elkrief, A., Desilets, A., Blanc-Durand, F., Cumbo, F., Blanco, A., Boidot, R., Chevrier, S., Daillère, R., Kroemer, G., Alla, L., Pons, N., Le Chatelier, E., Galleron, N., Roume, H., Dubuisson, A., Bouchard, N., Messaoudene, M., Drubay, D., Deutsch, E., Barlesi, F., Planchard, D., Segata, N., Martinez, S., Zitvogel, L., Soria, J.-C., & Besse, B.
Affiliations
  • Inserm (FR)
  • Centre Hospitalier de l’Université de Montréal (CA)
  • University of Trento (IT)
  • University of Trieste (IT)
  • Hôpital Foch (FR)
  • Sorbonne Paris Cité (FR)
  • Institut Gustave Roussy (FR)
  • Université de Lille (FR)
  • Hôpital Européen (FR)
  • Centre Georges François Leclerc (FR)
  • Université Paris-Saclay (FR)
  • Centre Hospitalier Universitaire de Sherbrooke (CA)
  • Centre Hospitalier Intercommunal Aix-Pertuis (FR)
Corresponding author
Zitvogel, Laurence
ORCID
Venue
Nature Medicine
Publisher
Springer Science and Business Media LLC
Published
2022-02
Volume
28
Issue
2
Pages
315-324
ISSN
  • 1078-8956 (ISSN-L)
  • 1546-170X
DOI
10.1038/s41591-021-01655-5
PMC
PMC9330544
OpenAlex
W4210773546
Cited by
685
References
65
Citations by year
2026: 146 · 2025: 187 · 2024: 151 · 2023: 148 · 2022: 52 · 2021: 1
FWCI
56.71
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • HAL (submittedVersion, other-oa)
  • ArTS Archivio della ricerca di Trieste (University of Trieste https://www.units.it/) (submittedVersion, other-oa)
  • HAL (submittedVersion)
  • Institutional Research Information System (Università degli Studi di Trento) (submittedVersion)
Funders
  • Amgen
  • Bristol-Myers Squibb
  • Eli Lilly and Company
  • Pfizer
  • AstraZeneca
  • GlaxoSmithKline
  • Sanofi
  • Cancer Prevention and Research Institute of Texas (RP170067)
  • Celgene
  • Association pour la Recherche sur le Cancer
  • Taiho Pharmaceutical
  • Novocure
  • Seerave Foundation
  • E-Rare
  • Relay Therapeutics
  • European Commission (716575, 825410, 818368)
  • Agence Nationale de la Recherche (2017-, ANR-10-LABX-0015, ANR-18-IBHU-0002, ANR-19-CE15-0029, ANR18, ANR-11-DPBS-0001, E-Rare-2, ANR-16-RHUS-0008)
  • Fondation Leducq
  • Institut National de la Santé et de la Recherche Médicale
  • Fondation pour la Recherche Médicale
  • Ministero dell’Istruzione, dell’Università e della Ricerca (H2020, RBFR13EWWI_001)
  • Fondation ARC pour la Recherche sur le Cancer
  • Ligue Contre le Cancer
  • Institut Universitaire de France
  • Institut National Du Cancer (19-CE15-0029-01, DGOS-Inserm_12551)
  • Institut Gustave-Roussy
  • Direction Générale de l’offre de Soins
  • Chancellerie des Universités de Paris
  • Servier
  • Fondation Gustave Roussy
  • Symphogen
  • Da Volterra
  • Institut Du Cancer de Montréal
  • National Institutes of Health (RP170067, 1u01ca230551-01a1, 1U01CA230551)
  • Genentech
  • Samsung
  • Horizon 2020 Framework Programme (MASTER-818368, OncoBiome 825410, 818368, 825410)
  • Canadian Institutes of Health Research
  • Labex Immuno-Oncology
  • National Cancer Institute (1U01CA230551, U01 CA230551, R01CA230551)
  • Institute of Cancer Research
  • Daiichi Sankyo Europe
Topics
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Ferroptosis and cancer prognosis
Keywords
Akkermansia muciniphila, non-small cell lung cancer, anti-PD-1 therapy, immune checkpoint inhibitors, predictive biomarkers, gut microbiota, PD-L1 expression, antibiotic use, Clostridium, tumor microenvironment, Eubacterium hallii, Bifidobacterium adolescentis, objective response rate, overall survival, patient stratification
MeSH terms
Akkermansia, Carcinoma, Non-Small-Cell Lung, Humans, Lung Neoplasms, Retrospective Studies, Tumor Microenvironment, B7-H1 Antigen, Programmed Cell Death 1 Receptor

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 2026-10-05.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-05.

Statistics and arithmetic are recomputed, not judged.

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