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

被引：3684

作者：

Routy, Bertrand ^{[1
,2
,3
,4
]}

Le Chatelier, Emmanuelle ^{[5
]}

Derosa, Lisa ^{[1
,2
,3
,4
]}

Duong, Connie P. M. ^{[1
,2
,3
,6
]}

Alou, Maryam Tidjani ^{[1
,2
,3
,4
]}

Daillere, Romain ^{[1
,2
,3
,4
]}

Fluckiger, Aurelie ^{[1
,2
,3
,6
]}

Messaoudene, Meriem ^{[1
,2
,3
]}

Rauber, Conrad ^{[1
,2
,3
,4
]}

Roberti, Maria P. ^{[1
,2
,3
,6
]}

Fidelle, Marine ^{[1
,4
,6
]}

Flament, Caroline ^{[1
,2
,3
,6
]}

Poirier-Colame, Vichnou ^{[1
,2
,3
,6
]}

Opolon, Paule ^{[7
]}

Klein, Christophe ^{[8
]}

Iribarren, Kristina ^{[9
,10
,11
,12
,13
]}

Mondragon, Laura ^{[9
,10
,11
,12
,13
]}

Jacquelot, Nicolas ^{[1
,2
,3
,4
]}

Qu, Bo ^{[1
,2
,3
,4
]}

Ferrere, Gladys ^{[1
,2
,3
,4
]}

Clemenson, Celine ^{[1
,14
,15
]}

Mezquita, Laura ^{[1
,16
]}

Masip, Jordi Remon ^{[1
,16
]}

Naltet, Charles ^{[17
]}

Brosseau, Solenn ^{[17
]}

Kaderbhai, Coureche ^{[18
]}

Richard, Corentin ^{[18
]}

Rizvi, Hira ^{[19
]}

Levenez, Florence ^{[5
]}

Galleron, Nathalie ^{[5
]}

Quinquis, Benoit ^{[5
]}

Pons, Nicolas ^{[5
]}

Ryffel, Bernhard ^{[20
]}

Minard-Colin, Veronique ^{[1
,21
]}

Gonin, Patrick ^{[1
,22
]}

Soria, Jean-Charles ^{[1
,16
]}

Deutsch, Eric ^{[1
,14
,15
]}

Loriot, Yohann ^{[1
,4
,16
]}

Ghiringhelli, Francois ^{[18
]}

Zalcman, Gerard ^{[17
]}

Goldwasser, Francois ^{[10
,23
,24
]}

Escudier, Bernard ^{[1
,16
,25
]}

Hellmann, Matthew D. ^{[26
,27
]}

Eggermont, Alexander ^{[1
,2
,3
,16
]}

Raoult, Didier ^{[28
]}

Albiges, Laurence ^{[1
,4
,16
]}

Kroemer, Guido ^{[9
,10
,11
,12
,13
,29
,30
]}

Zitvogel, Laurence ^{[1
,2
,3
,4
,6
]}

机构：

[1] GRCC, Villejuif, France

[2] INSERM, U1015, Villejuif, France

[3] Equipe Labellisee Ligue Natl Canc, Villejuif, France

[4] Univ Paris Saclay, Univ Paris Sud, Gustave Roussy, Villejuif, France

[5] Univ Paris Saclay, INRA, MGP MetaGenoPolis, Jouy En Josas, France

[6] Ctr Clin Invest Biotherapies Canc CICBT 1428, Villejuif, France

[7] Gustave Roussy, Lab Pathol Expt, F-94800 Villejuif, France

[8] Univ Paris 06, Univ Pierre & Marie Curie, Univ Paris Descartes,Sorbonne Univ, Ctr Rech Cordeliers,INSERM,Sorbonne Paris Cite,UM, Paris, France

[9] GRCC, Metabol & Cell Biol Platforms, Villejuif, France

[10] Paris Descartes Univ, Sorbonne Paris Cite, Paris, France

[11] Ctr Rech Cordeliers, Equipe Labellisee Ligue Natl Canc 11, Paris, France

[12] INSERM, U1138, Paris, France

[13] Univ Paris 06, Paris, France

[14] Univ Paris Saclay, Gustave Roussy, Dept Radiat Oncol, INSERM,U1030, F-94805 Villejuif, France

[15] Univ Paris Saclay, Gustave Roussy, Mol Radiotherapy, F-94805 Villejuif, France

[16] Gustave Roussy, Dept Med Oncol, Villejuif, France

[17] Univ Paris Diderot, Hosp Bichat Claude Bernard, AP HP, Thorac Oncol Dept,CIC1425 CLIP2 Paris Nord, Paris, France

[18] Ctr GF Leclerc, Dept Med Oncol, Dijon, France

[19] Mem Sloan Kettering Canc Ctr, Druckenmiller Ctr Lung Canc Res, 1275 York Ave, New York, NY 10021 USA

[20] Univ Orleans, Mol Immunol & Embryol, UMR 7355, CNRS, Orleans, France

[21] GRCC, Dept Pediat Oncol, Villejuif, France

[22] GRCC, Preclin Res Platform, Villejuif, France

[23] Cochin Hosp, AP HP, Dept Med Oncol, Paris, France

[24] Immunomodulatory Therapies Multidisciplinary Stud, Paris, France

[25] GRCC, INSERM, U981, Villejuif, France

[26] Mem Sloan Kettering Canc Ctr, Dept Med, Thorac Oncol Serv, 1275 York Ave, New York, NY 10021 USA

[27] Weill Cornell Med Coll, Dept Med, New York, NY USA

[28] Aix Marseille Univ, URMITE, CNRS, UM63 7278,IRD 198,INSERM 1095,IHU Mediterranee In, F-13005 Marseille, France

[29] Hop Europeen Georges Pompidou, AP HP, Pole Biol, Paris, France

[30] Karolinska Univ Hosp, Dept Womens & Childrens Hlth, S-17176 Stockholm, Sweden

来源：

SCIENCE | 2018年 / 359卷 / 6371期

基金：

欧洲研究理事会;

关键词：

CELL LUNG-CANCER; INTESTINAL MICROBIOTA; PD-1; BLOCKADE; ANTITUMOR IMMUNITY; NIVOLUMAB; MELANOMA; CYCLOPHOSPHAMIDE; MICROENVIRONMENT; RESISTANCE; GENES;

D O I：

10.1126/science.aan3706

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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 FMT with 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.

引用

页码：91 / +

页数：7

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