Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients

被引：3297

作者：

Gopalakrishnan, V. ^{[1
,2
]}

Spencer, C. N. ^{[2
,3
]}

Nezi, L. ^{[3
]}

Reuben, A. ^{[1
]}

Andrews, M. C. ^{[1
]}

Karpinets, T. V. ^{[3
]}

Prieto, P. A. ^{[1
,20
]}

Vicente, D. ^{[1
]}

Hoffman, K. ^{[4
]}

Wei, S. C. ^{[5
]}

Cogdill, A. P. ^{[1
,5
]}

Zhao, L. ^{[3
]}

Hudgens, C. W. ^{[6
]}

Hutchinson, D. S. ^{[7
]}

Manzo, T. ^{[3
]}

de Macedo, M. Petaccia ^{[6
,21
]}

Cotechini, T. ^{[8
]}

Kumar, T. ^{[3
]}

Chen, W. S. ^{[9
]}

Reddy, S. M. ^{[10
]}

Sloane, R. Szczepaniak ^{[1
]}

Galloway-Pena, J. ^{[11
]}

Jiang, H. ^{[1
]}

Chen, P. L. ^{[9
,22
]}

Shpall, E. J. ^{[12
]}

Rezvani, K. ^{[12
]}

Alousi, A. M. ^{[12
]}

Chemaly, R. F. ^{[11
]}

Shelburne, S. ^{[3
,11
]}

Vence, L. M. ^{[5
]}

Okhuysen, P. C. ^{[11
]}

Jensen, V. B. ^{[13
]}

Swennes, A. G. ^{[7
]}

McAllister, F. ^{[14
]}

Sanchez, E. Marcelo Riquelme ^{[14
]}

Zhang, Y. ^{[14
]}

Le Chatelier, E. ^{[15
]}

Zitvogel, L. ^{[16
]}

Pons, N. ^{[15
]}

Austin-Breneman, J. L. ^{[1
,23
]}

Haydu, L. E. ^{[1
]}

Burton, E. M. ^{[1
]}

Gardner, J. M. ^{[1
]}

Sirmans, E. ^{[17
]}

Hu, J. ^{[18
]}

Lazar, A. J. ^{[6
,9
]}

Tsujikawa, T. ^{[8
]}

Diab, A. ^{[17
]}

Tawbi, H. ^{[17
]}

Glitza, I. C. ^{[17
]}

机构：

[1] Univ Texas MD Anderson Canc Ctr, Dept Surg Oncol, Houston, TX 77030 USA

[2] Univ Texas Houston, Sch Publ Hlth, Dept Epidemiol Human Genet & Environm Sci, Houston, TX 77030 USA

[3] Univ Texas MD Anderson Canc Ctr, Dept Genom Med, Houston, TX 77030 USA

[4] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA

[5] Univ Texas MD Anderson Canc Ctr, Dept Immunol, Houston, TX 77030 USA

[6] Univ Texas MD Anderson Canc Ctr, Dept Translat Mol Pathol, Houston, TX 77030 USA

[7] Baylor Coll Med, Dept Mol Virol & Microbiol, Houston, TX 77030 USA

[8] Oregon Hlth & Sci Univ, Dept Cell Dev & Cell Biol, Portland, OR 97239 USA

[9] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA

[10] Univ Texas MD Anderson Canc Ctr, Dept Breast Med Oncol, Houston, TX 77030 USA

[11] Univ Texas MD Anderson Canc Ctr, Dept Infect Dis, Houston, TX 77030 USA

[12] Univ Texas MD Anderson Canc Ctr, Dept Stem Cell Transplantat, Houston, TX 77030 USA

[13] Univ Texas MD Anderson Canc Ctr, Dept Vet Med & Surg, Houston, TX 77030 USA

[14] Univ Texas MD Anderson Canc Ctr, Dept Clin Canc Prevent, Houston, TX 77030 USA

[15] Inst Natl Rech Agronom, Ctr Rech Jouy En Josas, F-78352 Jouy En Josas, France

[16] Inst Gustave Roussy, Ctr Invest Clin Biotherapie, F-94805 Villejuif, France

[17] Univ Texas MD Anderson Canc Ctr, Dept Melanoma Med Oncol, Houston, TX 77030 USA

[18] Univ Texas MD Anderson Canc Ctr, Dept Biostat, Houston, TX 77030 USA

[19] Univ Texas MD Anderson Canc Ctr, Dept Genitourinary Med Oncol, Houston, TX 77030 USA

[20] Univ Rochester, James P Wilmot Canc Ctr, Rochester, NY 14642 USA

[21] AC Camargo Canc Ctr, Sao Paulo, Brazil

[22] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL 33612 USA

[23] Harvard Univ, Cambridge, MA 02138 USA

[24] MedImmune, Gaithersburg, MD 20878 USA

来源：

SCIENCE | 2018年 / 359卷 / 6371期

关键词：

INTESTINAL MICROBIOTA; CTLA-4; BLOCKADE; PD-1; CANCER; THERAPY; SENSITIVITY; MECHANISMS; IPILIMUMAB; DIVERSITY; NIVOLUMAB;

D O I：

10.1126/science.aan4236

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：

Preclinical mouse models suggest that the gut microbiome modulates tumor response to checkpoint blockade immunotherapy; however, this has not been well-characterized in human cancer patients. Here we examined the oral and gut microbiome of melanoma patients undergoing anti-programmed cell death 1 protein (PD-1) immunotherapy (n = 112). Significant differences were observed in the diversity and composition of the patient gut microbiome of responders versus nonresponders. Analysis of patient fecal microbiome samples (n = 43, 30 responders, 13 nonresponders) showed significantly higher alpha diversity (P < 0.01) and relative abundance of bacteria of the Ruminococcaceae family (P < 0.01) in responding patients. Metagenomic studies revealed functional differences in gut bacteria in responders, including enrichment of anabolic pathways. Immune profiling suggested enhanced systemic and antitumor immunity in responding patients with a favorable gut microbiome as well as in germ-free mice receiving fecal transplants from responding patients. Together, these data have important implications for the treatment of melanoma patients with immune checkpoint inhibitors.

引用

页码：97 / 103

页数：7

共 38 条

[1] Haematological malignancies: at the forefront of immunotherapeutic innovation [J].

Bachireddy, Pavan ;

Burkhardt, Ute E. ;

Rajasagi, Mohini ;

Wu, Catherine J. .

NATURE REVIEWS CANCER, 2015, 15 (04) :201-215

[2] Microbiome-Modulated Metabolites at the Interface of Host Immunity [J].

Blacher, Eran ;

Levy, Maayan ;

Tatirovsky, Evgeny ;

Elinav, Eran .

JOURNAL OF IMMUNOLOGY, 2017, 198 (02) :572-580

[3]

Caspi R, 2008, NUCLEIC ACIDS RES, V36, pD623, DOI [10.1093/nar/gkm900, 10.1093/nar/gkt1103]

[4] Baseline gut microbiota predicts clinical response and colitis in metastatic melanoma patients treated with ipilimumab [J].

Chaput, N. ;

Lepage, P. ;

Coutzac, C. ;

Soularue, E. ;

Le Roux, K. ;

Monot, C. ;

Boselli, L. ;

Routier, E. ;

Cassard, L. ;

Collins, M. ;

Vaysse, T. ;

Marthey, L. ;

Eggermont, A. ;

Asvatourian, V. ;

Lanoy, E. ;

Mateus, C. ;

Robert, C. ;

Carbonnel, F. .

ANNALS OF ONCOLOGY, 2017, 28 (06) :1368-1379

[5] Analysis of Immune Signatures in Longitudinal Tumor Samples Yields Insight into Biomarkers of Response and Mechanisms of Resistance to Immune Checkpoint Blockade [J].

Chen, Pei-Ling ;

Roh, Whijae ;

Reuben, Alexandre ;

Cooper, Zachary A. ;

Spencer, Christine N. ;

Prieto, Peter A. ;

Miller, John P. ;

Bassett, Roland L. ;

Gopalakrishnan, Vancheswaran ;

Wani, Khalida ;

De Macedo, Mariana Petaccia ;

Austin-Breneman, Jacob L. ;

Jiang, Hong ;

Chang, Qing ;

Reddy, Sangeetha M. ;

Chen, Wei-Shen ;

Tetzlaff, Michael T. ;

Broaddus, Russell J. ;

Davies, Michael A. ;

Gershenwald, Jeffrey E. ;

Haydu, Lauren ;

Lazar, Alexander J. ;

Patel, Sapna P. ;

Hwu, Patrick ;

Hwu, Wen-Jen ;

Diab, Adi ;

Glitza, Isabella C. ;

Woodman, Scott E. ;

Vence, Luis M. ;

Wistuba, Ignacio I. ;

Amaria, Rodabe N. ;

Kwong, Lawrence N. ;

Prieto, Victor ;

Davis, R. Eric ;

Ma, Wencai ;

Overwijk, Willem W. ;

Sharpe, Arlene H. ;

Hu, Jianhua ;

Futreal, P. Andrew ;

Blando, Jorge ;

Sharma, Padmanee ;

Allison, James P. ;

Chin, Lynda ;

Wargo, Jennifer A. .

CANCER DISCOVERY, 2016, 6 (08) :827-837

[6] Sporadic colorectal cancer: microbial contributors to disease prevention, development and therapy [J].

Drewes, Julia L. ;

Housseau, Franck ;

Sears, Cynthia L. .

BRITISH JOURNAL OF CANCER, 2016, 115 (03) :273-280

[7] Cancer and the microbiota [J].

Garrett, Wendy S. .

SCIENCE, 2015, 348 (6230) :80-86

[8] Genomic and Transcriptomic Features of Response to Anti-PD-1 Therapy in Metastatic Melanoma [J].

Hugo, Willy ;

Zaretsky, Jesse M. ;

Sun, Lu ;

Song, Chunying ;

Moreno, Blanca Homet ;

Hu-Lieskovan, Siwen ;

Berent-Maoz, Beata ;

Pang, Jia ;

Chmielowski, Bartosz ;

Cherry, Grace ;

Seja, Elizabeth ;

Lomeli, Shirley ;

Kong, Xiangju ;

Kelley, Mark C. ;

Sosman, Jeffrey A. ;

Johnson, Douglas B. ;

Ribas, Antoni ;

Lo, Roger S. .

CELL, 2016, 165 (01) :35-44

[9] Structure, function and diversity of the healthy human microbiome [J].

Huttenhower, Curtis ;

Gevers, Dirk ;

Knight, Rob ;

Abubucker, Sahar ;

Badger, Jonathan H. ;

Chinwalla, Asif T. ;

Creasy, Heather H. ;

Earl, Ashlee M. ;

FitzGerald, Michael G. ;

Fulton, Robert S. ;

Giglio, Michelle G. ;

Hallsworth-Pepin, Kymberlie ;

Lobos, Elizabeth A. ;

Madupu, Ramana ;

Magrini, Vincent ;

Martin, John C. ;

Mitreva, Makedonka ;

Muzny, Donna M. ;

Sodergren, Erica J. ;

Versalovic, James ;

Wollam, Aye M. ;

Worley, Kim C. ;

Wortman, Jennifer R. ;

Young, Sarah K. ;

Zeng, Qiandong ;

Aagaard, Kjersti M. ;

Abolude, Olukemi O. ;

Allen-Vercoe, Emma ;

Alm, Eric J. ;

Alvarado, Lucia ;

Andersen, Gary L. ;

Anderson, Scott ;

Appelbaum, Elizabeth ;

Arachchi, Harindra M. ;

Armitage, Gary ;

Arze, Cesar A. ;

Ayvaz, Tulin ;

Baker, Carl C. ;

Begg, Lisa ;

Belachew, Tsegahiwot ;

Bhonagiri, Veena ;

Bihan, Monika ;

Blaser, Martin J. ;

Bloom, Toby ;

Bonazzi, Vivien ;

Brooks, J. Paul ;

Buck, Gregory A. ;

Buhay, Christian J. ;

Busam, Dana A. ;

Campbell, Joseph L. .

NATURE, 2012, 486 (7402) :207-214

[10] Commensal Bacteria Control Cancer Response to Therapy by Modulating the Tumor Microenvironment [J].

Iida, Noriho ;

Dzutsev, Amiran ;

Stewart, C. Andrew ;

Smith, Loretta ;

Bouladoux, Nicolas ;

Weingarten, Rebecca A. ;

Molina, Daniel A. ;

Salcedo, Rosalba ;

Back, Timothy ;

Cramer, Sarah ;

Dai, Ren-Ming ;

Kiu, Hiu ;

Cardone, Marco ;

Naik, Shruti ;

Patri, Anil K. ;

Wang, Ena ;

Marincola, Francesco M. ;

Frank, Karen M. ;

Belkaid, Yasmine ;

Trinchieri, Giorgio ;

Goldszmid, Romina S. .

SCIENCE, 2013, 342 (6161) :967-970

← 1 2 3 4 →