Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota

被引:2804
作者
Vetizou, Marie [1 ,2 ,3 ]
Pitt, Jonathan M. [1 ,2 ,3 ]
Daillere, Romain [1 ,2 ,3 ]
Lepage, Patricia [4 ]
Waldschmitt, Nadine [5 ]
Flament, Caroline [1 ,2 ,6 ]
Rusakiewicz, Sylvie [1 ,2 ,6 ]
Routy, Bertrand [1 ,2 ,3 ,6 ]
Roberti, Maria P. [1 ,2 ,6 ]
Duong, Connie P. M. [1 ,2 ,6 ]
Poirier-Colame, Vichnou [1 ,2 ,6 ]
Roux, Antoine [1 ,2 ,7 ]
Becharef, Sonia [1 ,2 ,6 ]
Formenti, Silvia [8 ]
Golden, Encouse [8 ]
Cording, Sascha [9 ]
Eberl, Gerard [9 ]
Schlitzer, Andreas [10 ]
Ginhoux, Florent [10 ]
Mani, Sridhar [11 ,12 ]
Yamazaki, Takahiro [1 ,2 ]
Jacquelot, Nicolas [1 ,2 ,3 ]
Enot, David P. [1 ,13 ]
Berard, Marion [14 ]
Nigou, Jerome [15 ,16 ]
Opolon, Paule [1 ]
Eggermont, Alexander [1 ,2 ,17 ]
Woerther, Paul-Louis [18 ]
Chachaty, Elisabeth [18 ]
Chaput, Nathalie [1 ,19 ]
Robert, Caroline [1 ,20 ]
Mateus, Christina [1 ]
Kroemer, Guido [13 ,21 ,22 ,23 ]
Raoult, Didier [24 ]
Boneca, Ivo Gomperts [25 ,26 ]
Carbonnel, Franck [27 ]
Chamaillard, Mathias
Zitvogel, Laurence [1 ,2 ,3 ,6 ]
机构
[1] Inst Cancerol Gustave Roussy Canc Campus GRCC, 114 Rue Edouard, F-94805 Villejuif, France
[2] GRCC, INSERM, U1015, Villejuif, France
[3] Univ Paris Sud, Univ Paris 11, Le Kremlin Bicetre, France
[4] INRA, Micalis UMR1319, F-78360 Jouy En Josas, France
[5] Univ Lille, Ctr Hosp Reg Univ Lille, Inst Pasteur Lille,CNRS,INSERM, U1019,UMR 8204,Ctr Infect Immunite Lille CIIL, F-59000 Lille, France
[6] Ctr Clin Invest Biotherapies Canc 1428, Villejuif, France
[7] Univ Paris 05, Sorbonne Paris Cite, Paris, France
[8] NYU, Dept Radiat Oncol, New York, NY USA
[9] Inst Pasteur, Microenvironm & Immun Unit, Paris, France
[10] Agcy Sci Technol & Res, A STAR, Singapore Immunol Network SIgN, Singapore, Singapore
[11] Albert Einstein Coll Med, Dept Genet, Bronx, NY 10461 USA
[12] Albert Einstein Coll Med, Dept Med, Bronx, NY 10461 USA
[13] GRCC, Metab Platform, Villejuif, France
[14] Inst Pasteur, Animalerie Cent, Paris, France
[15] Inst Pharmacol & Biol Struct IPBS, CNRS, Toulouse, France
[16] Univ Paul Sabatier, Univ Toulouse, IPBS, F-31077 Toulouse, France
[17] Inst Gustave Roussy, Dept Med Oncol, Villejuif, France
[18] GRCC, Serv Microbiol, Villejuif, France
[19] GRCC, CNRS, INSERM, US 23,Lab Immunomonitoring Oncol,UMS 3655, Villejuif, France
[20] GRCC, INSERM, U981, Villejuif, France
[21] INSERM, U848, Villejuif, France
[22] Ctr Rech Cordeliers, Equipe Labellisee Ligue Natl Canc 11, INSERM, U1138, Paris, France
[23] Assistance Publ Hop Paris, Hop Europeen Georges Pom, Pole Biol, Paris, France
[24] Aix Marseille Univ, Univ Mediterranee, Fac Med, Unite Rickettsies, Marseille, France
[25] Inst Pasteur, Unit Biol & Genet Bacterial Cell Wall, Paris, France
[26] INSERM, Equipe Avenir, Paris, France
[27] Assistance Publ Hop Paris, Hop Bicetre, Dept Gastroenterol, Paris, France
基金
欧洲研究理事会;
关键词
T-CELLS; ANTIBODY; MOLECULE; CANCER; INNATE; MODEL;
D O I
10.1126/science.aad1329
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
Antibodies targeting CTLA-4 have been successfully used as cancer immunotherapy. We find that the antitumor effects of CTLA-4 blockade depend on distinct Bacteroides species. In mice and patients, Tcell responses specific for B. thetaiotaomicron or B. fragilis were associated with the efficacy of CTLA-4 blockade. Tumors in antibiotic-treated or germ-free mice did not respond to CTLA blockade. This defect was overcome by gavage with B. fragilis, by immunization with B. fragilis polysaccharides, or by adoptive transfer of B. fragilis-specific T cells. Fecal microbial transplantation from humans to mice confirmed that treatment of melanoma patients with antibodies against CTLA-4 favored the outgrowth of B. fragilis with anticancer properties. This study reveals a key role for Bacteroidales in the immunostimulatory effects of CTLA-4 blockade.
引用
收藏
页码:1079 / +
页数:7
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