Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors

Bertrand Routy; Emmanuelle Le Chatelier; Lisa Derosa; Connie P.M. Duong; Maryam Tidjani Alou; Romain Daillère; Aurélie Fluckiger; Meriem Messaoudene; Conrad Rauber; Maria P. Roberti; Marine Fidelle; Caroline Flament; Vichnou Poirier-Colame; Paule Opolon; Christophe Klein; Kristina Iribarren; Laura Mondragón; Nicolas Jacquelot; Bo Qu; Gladys Ferrere; Céline Clémenson; Laura Mezquita; Jordi Remon Masip; Charles Naltet; Solenn Brosseau; Coureche Kaderbhai; Corentin Richard; Hira Rizvi; Florence Levenez; Nathalie Galleron; Benoit Quinquis; Nicolas Pons; Bernhard Ryffel; Véronique Minard-Colin; Patrick Gonin; Jean Charles Soria; Eric Deutsch; Yohann Loriot; François Ghiringhelli; Gérard Zalcman; François Goldwasser; Bernard Escudier; Matthew D. Hellmann; Alexander Eggermont; Didier Raoult; Laurence Albiges; Guido Kroemer; Laurence Zitvogel

doi:10.1126/science.aan3706

Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors

Bertrand Routy, Emmanuelle Le Chatelier, Lisa Derosa, Connie P.M. Duong, Maryam Tidjani Alou, Romain Daillère, Aurélie Fluckiger, Meriem Messaoudene, Conrad Rauber, Maria P. Roberti, Marine Fidelle, Caroline Flament, Vichnou Poirier-Colame, Paule Opolon, Christophe Klein, Kristina Iribarren, Laura Mondragón, Nicolas Jacquelot, Bo Qu, Gladys FerrereCéline Clémenson, Laura Mezquita, Jordi Remon Masip, Charles Naltet, Solenn Brosseau, Coureche Kaderbhai, Corentin Richard, Hira Rizvi, Florence Levenez, Nathalie Galleron, Benoit Quinquis, Nicolas Pons, Bernhard Ryffel, Véronique Minard-Colin, Patrick Gonin, Jean Charles Soria, Eric Deutsch, Yohann Loriot, François Ghiringhelli, Gérard Zalcman, François Goldwasser, Bernard Escudier, Matthew D. Hellmann, Alexander Eggermont, Didier Raoult, Laurence Albiges, Guido Kroemer, Laurence Zitvogel

Onderzoeksoutput: Bijdrage aan tijdschrift › Artikel › peer review

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Immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis induce sustained clinical responses in a sizable minority of cancer patients.We found that primary resistance to ICIs can be attributed to abnormal gut microbiome composition. Antibiotics inhibited the clinical benefit of ICIs in patients with advanced cancer. Fecal microbiota transplantation (FMT) from cancer patients who responded to ICIs into germ-free or antibiotic-treated mice ameliorated the antitumor effects of PD-1 blockade, whereas FMT from nonresponding patients failed to do so. Metagenomics of patient stool samples at diagnosis revealed correlations between clinical responses to ICIs and the relative abundance of Akkermansia muciniphila. Oral supplementation with A. muciniphila after FMTwith nonresponder feces restored the efficacy of PD-1 blockade in an interleukin-12-dependent manner by increasing the recruitment of CCR9+CXCR3+CD4+ T lymphocytes into mouse tumor beds.

Originele taal-2	Engels
Pagina's (van-tot)	91-97
Aantal pagina's	7
Tijdschrift	Science
Volume	359
Nummer van het tijdschrift	6371
DOI's	https://doi.org/10.1126/science.aan3706
Status	Gepubliceerd - 5 jan. 2018
Extern gepubliceerd	Ja

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10.1126/science.aan3706

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Routy, B., Le Chatelier, E., Derosa, L., Duong, C. P. M., Alou, M. T., Daillère, R., Fluckiger, A., Messaoudene, M., Rauber, C., Roberti, M. P., Fidelle, M., Flament, C., Poirier-Colame, V., Opolon, P., Klein, C., Iribarren, K., Mondragón, L., Jacquelot, N., Qu, B., ... Zitvogel, L. (2018). Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science, 359(6371), 91-97. https://doi.org/10.1126/science.aan3706

@article{623be0bcf2fd4e72b2c360b175df4bf0,

title = "Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors",

abstract = "Immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis induce sustained clinical responses in a sizable minority of cancer patients.We found that primary resistance to ICIs can be attributed to abnormal gut microbiome composition. Antibiotics inhibited the clinical benefit of ICIs in patients with advanced cancer. Fecal microbiota transplantation (FMT) from cancer patients who responded to ICIs into germ-free or antibiotic-treated mice ameliorated the antitumor effects of PD-1 blockade, whereas FMT from nonresponding patients failed to do so. Metagenomics of patient stool samples at diagnosis revealed correlations between clinical responses to ICIs and the relative abundance of Akkermansia muciniphila. Oral supplementation with A. muciniphila after FMTwith nonresponder feces restored the efficacy of PD-1 blockade in an interleukin-12-dependent manner by increasing the recruitment of CCR9+CXCR3+CD4+ T lymphocytes into mouse tumor beds.",

author = "Bertrand Routy and {Le Chatelier}, Emmanuelle and Lisa Derosa and Duong, {Connie P.M.} and Alou, {Maryam Tidjani} and Romain Daill{\`e}re and Aur{\'e}lie Fluckiger and Meriem Messaoudene and Conrad Rauber and Roberti, {Maria P.} and Marine Fidelle and Caroline Flament and Vichnou Poirier-Colame and Paule Opolon and Christophe Klein and Kristina Iribarren and Laura Mondrag{\'o}n and Nicolas Jacquelot and Bo Qu and Gladys Ferrere and C{\'e}line Cl{\'e}menson and Laura Mezquita and Masip, {Jordi Remon} and Charles Naltet and Solenn Brosseau and Coureche Kaderbhai and Corentin Richard and Hira Rizvi and Florence Levenez and Nathalie Galleron and Benoit Quinquis and Nicolas Pons and Bernhard Ryffel and V{\'e}ronique Minard-Colin and Patrick Gonin and Soria, {Jean Charles} and Eric Deutsch and Yohann Loriot and Fran{\c c}ois Ghiringhelli and G{\'e}rard Zalcman and Fran{\c c}ois Goldwasser and Bernard Escudier and Hellmann, {Matthew D.} and Alexander Eggermont and Didier Raoult and Laurence Albiges and Guido Kroemer and Laurence Zitvogel",

note = "Funding Information: Archive (EMBL-EBI) under accession number PRJEB22863. B.R. was supported by Gustave Roussy Course of Excellence in Oncology–Fondation Philanthropia and a McGill University Townsend hematology research fellowship award. L.Z. and G.K. were supported by the Ligue contre le Cancer ({\'e}quipe labelis{\'e}e), Agence Nationale de la Recherche (ANR)–Projets blancs, ANR under the frame of E-Rare-2 (ERA-Net for Research on Rare Diseases), Association pour la recherche sur le cancer (ARC), Canc{\'e}rop{\^o}le Ile-de-France, Institut National du Cancer (INCa), Institut Universitaire de France, Fondation pour la Recherche M{\'e}dicale (FRM), the European Commission (ArtForce), the European Research Council (ERC), the LeDucq Foundation, LabEx Immuno-Oncology, SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE), SIRIC Cancer Research and Personalized Medicine (CARPEM), the Paris Alliance of Cancer Research Institutes (PACRI), and philanthropia (E. Badinter and N. Meyer). L.Z., E.L.C., and B.R. are inventors on patent EP17305206 and European license 16306779.6 held by Institut Gustave Roussy that covers use of microbial modulators for PD1/PD-L1/PD-L2 mAb-based treatments. L.Z. and G.K. are cofounders of EverImmune, a biotech company focused on the use of commensal bacteria for cancer treatment.",

year = "2018",

month = jan,

day = "5",

doi = "10.1126/science.aan3706",

language = "English",

volume = "359",

pages = "91--97",

journal = "Science",

issn = "0036-8075",

publisher = "American Association for the Advancement of Science",

number = "6371",

}

Routy, B, Le Chatelier, E, Derosa, L, Duong, CPM, Alou, MT, Daillère, R, Fluckiger, A, Messaoudene, M, Rauber, C, Roberti, MP, Fidelle, M, Flament, C, Poirier-Colame, V, Opolon, P, Klein, C, Iribarren, K, Mondragón, L, Jacquelot, N, Qu, B, Ferrere, G, Clémenson, C, Mezquita, L, Masip, JR, Naltet, C, Brosseau, S, Kaderbhai, C, Richard, C, Rizvi, H, Levenez, F, Galleron, N, Quinquis, B, Pons, N, Ryffel, B, Minard-Colin, V, Gonin, P, Soria, JC, Deutsch, E, Loriot, Y, Ghiringhelli, F, Zalcman, G, Goldwasser, F, Escudier, B, Hellmann, MD, Eggermont, A, Raoult, D, Albiges, L, Kroemer, G & Zitvogel, L 2018, 'Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors', Science, vol. 359, nr. 6371, blz. 91-97. https://doi.org/10.1126/science.aan3706

TY - JOUR

T1 - Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors

AU - Routy, Bertrand

AU - Le Chatelier, Emmanuelle

AU - Derosa, Lisa

AU - Duong, Connie P.M.

AU - Alou, Maryam Tidjani

AU - Daillère, Romain

AU - Fluckiger, Aurélie

AU - Messaoudene, Meriem

AU - Rauber, Conrad

AU - Roberti, Maria P.

AU - Fidelle, Marine

AU - Flament, Caroline

AU - Poirier-Colame, Vichnou

AU - Opolon, Paule

AU - Klein, Christophe

AU - Iribarren, Kristina

AU - Mondragón, Laura

AU - Jacquelot, Nicolas

AU - Qu, Bo

AU - Ferrere, Gladys

AU - Clémenson, Céline

AU - Mezquita, Laura

AU - Masip, Jordi Remon

AU - Naltet, Charles

AU - Brosseau, Solenn

AU - Kaderbhai, Coureche

AU - Richard, Corentin

AU - Rizvi, Hira

AU - Levenez, Florence

AU - Galleron, Nathalie

AU - Quinquis, Benoit

AU - Pons, Nicolas

AU - Ryffel, Bernhard

AU - Minard-Colin, Véronique

AU - Gonin, Patrick

AU - Soria, Jean Charles

AU - Deutsch, Eric

AU - Loriot, Yohann

AU - Ghiringhelli, François

AU - Zalcman, Gérard

AU - Goldwasser, François

AU - Escudier, Bernard

AU - Hellmann, Matthew D.

AU - Eggermont, Alexander

AU - Raoult, Didier

AU - Albiges, Laurence

AU - Kroemer, Guido

AU - Zitvogel, Laurence

N1 - Funding Information: Archive (EMBL-EBI) under accession number PRJEB22863. B.R. was supported by Gustave Roussy Course of Excellence in Oncology–Fondation Philanthropia and a McGill University Townsend hematology research fellowship award. L.Z. and G.K. were supported by the Ligue contre le Cancer (équipe labelisée), Agence Nationale de la Recherche (ANR)–Projets blancs, ANR under the frame of E-Rare-2 (ERA-Net for Research on Rare Diseases), Association pour la recherche sur le cancer (ARC), Cancéropôle Ile-de-France, Institut National du Cancer (INCa), Institut Universitaire de France, Fondation pour la Recherche Médicale (FRM), the European Commission (ArtForce), the European Research Council (ERC), the LeDucq Foundation, LabEx Immuno-Oncology, SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE), SIRIC Cancer Research and Personalized Medicine (CARPEM), the Paris Alliance of Cancer Research Institutes (PACRI), and philanthropia (E. Badinter and N. Meyer). L.Z., E.L.C., and B.R. are inventors on patent EP17305206 and European license 16306779.6 held by Institut Gustave Roussy that covers use of microbial modulators for PD1/PD-L1/PD-L2 mAb-based treatments. L.Z. and G.K. are cofounders of EverImmune, a biotech company focused on the use of commensal bacteria for cancer treatment.

PY - 2018/1/5

Y1 - 2018/1/5

N2 - Immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis induce sustained clinical responses in a sizable minority of cancer patients.We found that primary resistance to ICIs can be attributed to abnormal gut microbiome composition. Antibiotics inhibited the clinical benefit of ICIs in patients with advanced cancer. Fecal microbiota transplantation (FMT) from cancer patients who responded to ICIs into germ-free or antibiotic-treated mice ameliorated the antitumor effects of PD-1 blockade, whereas FMT from nonresponding patients failed to do so. Metagenomics of patient stool samples at diagnosis revealed correlations between clinical responses to ICIs and the relative abundance of Akkermansia muciniphila. Oral supplementation with A. muciniphila after FMTwith nonresponder feces restored the efficacy of PD-1 blockade in an interleukin-12-dependent manner by increasing the recruitment of CCR9+CXCR3+CD4+ T lymphocytes into mouse tumor beds.

AB - Immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis induce sustained clinical responses in a sizable minority of cancer patients.We found that primary resistance to ICIs can be attributed to abnormal gut microbiome composition. Antibiotics inhibited the clinical benefit of ICIs in patients with advanced cancer. Fecal microbiota transplantation (FMT) from cancer patients who responded to ICIs into germ-free or antibiotic-treated mice ameliorated the antitumor effects of PD-1 blockade, whereas FMT from nonresponding patients failed to do so. Metagenomics of patient stool samples at diagnosis revealed correlations between clinical responses to ICIs and the relative abundance of Akkermansia muciniphila. Oral supplementation with A. muciniphila after FMTwith nonresponder feces restored the efficacy of PD-1 blockade in an interleukin-12-dependent manner by increasing the recruitment of CCR9+CXCR3+CD4+ T lymphocytes into mouse tumor beds.

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U2 - 10.1126/science.aan3706

DO - 10.1126/science.aan3706

M3 - Article

C2 - 29097494

AN - SCOPUS:85033576428

SN - 0036-8075

VL - 359

SP - 91

EP - 97

JO - Science

JF - Science

IS - 6371

ER -

Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors

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