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

被引：409

作者：

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

Routy, Bertrand ^{[5
,6
]}

Thomas, Andrew Maltez ^{[7
,8
]}

Iebba, Valerio ^{[9
]}

Zalcman, Gerard ^{[10
]}

Friard, Sylvie ^{[11
]}

Mazieres, Julien ^{[12
]}

Audigier-Valette, Clarisse ^{[13
]}

Moro-Sibilot, Denis ^{[14
]}

Goldwasser, Francois ^{[15
,16
,17
]}

Silva, Carolina Alves Costa ^{[1
,2
]}

Terrisse, Safae ^{[1
]}

Bonvalet, Melodie ^{[1
]}

Scherpereel, Arnaud ^{[18
]}

Pegliasco, Herve ^{[19
]}

Richard, Corentin ^{[5
,6
]}

Ghiringhelli, Francois ^{[20
,21
,22
]}

Elkrief, Arielle ^{[5
,6
]}

Desilets, Antoine ^{[5
,6
]}

Blanc-Durand, Felix ^{[1
]}

Cumbo, Fabio ^{[7
]}

Blanco, Aitor ^{[7
]}

Boidot, Romain ^{[23
]}

Chevrier, Sandy ^{[23
]}

Daillere, Romain ^{[24
]}

Kroemer, Guido ^{[1
,15
,25
,26
,27
]}

Alla, Laurie ^{[28
]}

Pons, Nicolas ^{[28
]}

Le Chatelier, Emmanuelle ^{[28
]}

Galleron, Nathalie ^{[28
]}

Roume, Hugo ^{[28
]}

Dubuisson, Agathe ^{[1
]}

Bouchard, Nicole ^{[29
]}

Messaoudene, Meriem ^{[5
,6
]}

Drubay, Damien ^{[30
]}

Deutsch, Eric ^{[1
,4
,31
,32
]}

Barlesi, Fabrice ^{[1
,2
]}

Planchard, David ^{[1
,2
]}

Segata, Nicola ^{[7
,8
]}

Martinez, Stephanie ^{[33
]}

Zitvogel, Laurence ^{[1
,3
,4
,34
]}

Soria, Jean-Charles ^{[1
]}

Besse, Benjamin ^{[1
,2
,4
]}

机构：

[1] Gustave Roussy Canc Campus, Villejuif, France

[2] Gustave Roussy, Canc Med Dept, Villejuif, France

[3] Inst Natl Sante & Rech Med INSERM U1015, Ligue Natl Canc, Equipe Labellisee, Villejuif, France

[4] Univ Paris Saclay, Ile De France, France

[5] Ctr Hosp Univ Montreal CHUM, Dept Med, Hematol Oncol Div, Montreal, PQ, Canada

[6] Ctr Rech CHUM CRCHUM, Montreal, PQ, Canada

[7] Univ Trento, Dept CIBIO, Trento, Italy

[8] European Inst Oncol IEO IRCCS, Milan, Italy

[9] Univ Trieste, Dept Med Surg & Hlth Sci, Trieste, Italy

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

[11] Foch Hosp, Pneumol Dept, Suresnes, France

[12] Toulouse Univ Hosp, Dept Pneumol, Toulouse, France

[13] Ctr Hosp Toulon St Musse, Pneumol Dept, Toulon, France

[14] Ctr Hosp Univ, Dept Thorac Oncol, Grenoble, France

[15] Paris Descartes Univ, Sorbonne Paris Cite, UPR 4466, Paris, France

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

[17] Immunomodulatory Therapies Multidisciplinary Stud, Paris, France

[18] Univ Lille, Univ Hosp CHU, Dept Pulm & Thorac Oncol, Lille, France

[19] European Hosp, Pulm Dept, Marseille, France

[20] Ctr Georges Francois Leclerc, Canc Biol Transfer Platform, Dijon, France

[21] Ctr Rech INSERM LNC UMR1231, Dijon, France

[22] Ctr Georges Francois Leclerc, Dept Med Oncol, Dijon, France

[23] UNICANCER, Dept Biol & Pathol Tumors, Unit Mol Biol, Georges Francois Leclerc Canc Ctr, Dijon, France

[24] Gustave Roussy Canc Campus, Everlmmune, Villejuif, France

[25] Univ Paris, Inst Univ France, Ctr Rech Cordeliers, Equipe Labellisee Ligue Canc,INSERM U1138, Paris, France

[26] Inst Gustave Roussy, Metabol & Cell Biol Platforms, Villejuif, France

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

[28] Univ Paris Saclay, MGP, INRAE, Jouy En Josas, France

[29] Ctr Hosp Sherbrooke, Sherbrooke, PQ, Canada

[30] Oncostat, INSERM U1018, Villejuif, France

[31] Gustave Roussy, Dept Radiat Oncol, Villejuif, France

[32] INSERM U1030, Radiotherapie Mol & Innovat Therapeut, Villejuif, France

[33] Ctr Hosp Aix En Provence, Serv Malad Resp, Aix En Provence, France

[34] Ctr Clin Invest Biotherapies Canc BIOTHERIS 1428, Villejuif, France

来源：

NATURE MEDICINE | 2022年 / 28卷 / 02期

基金：

欧洲研究理事会; 加拿大健康研究院; 欧盟地平线“2020”; 美国国家卫生研究院;

关键词：

GUT; IMMUNOTHERAPY; MICROBIOME; INHIBITION; DOCETAXEL; NIVOLUMAB; ELEMENTS; OUTCOMES;

D O I：

10.1038/s41591-021-01655-5

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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. In a large multicentric study of patients with advanced NSCLC undergoing anti-PD-1 therapy, the relative abundance of intestinal Akkermansia spp. was shown to associate with changes in the gut microbiome ecosystem and clinical outcomes.

引用

页码：315 / +

页数：27

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