Cross-cohort gut microbiome associations with immune checkpoint inhibitor response in advanced melanoma

Karla A. Lee; Andrew Maltez Thomas; Laura A. Bolte; Johannes R. Björk; Laura Kist de Ruijter; Federica Armanini; Francesco Asnicar; Aitor Blanco-Miguez; Ruth Board; Neus Calbet-Llopart; Lisa Derosa; Nathalie Dhomen; Kelly Brooks; Mark Harland; Mark Harries; Emily R. Leeming; Paul Lorigan; Paolo Manghi; Richard Marais; Julia Newton-Bishop; Luigi Nezi; Federica Pinto; Miriam Potrony; Susana Puig; Patricio Serra-Bellver; Heather M. Shaw; Sabrina Tamburini; Sara Valpione; Amrita Vijay; Levi Waldron; Laurence Zitvogel; Moreno Zolfo; Elisabeth G.E. de Vries; Paul Nathan; Rudolf S.N. Fehrmann; Véronique Bataille; Geke A.P. Hospers; Tim D. Spector; Rinse K. Weersma; Nicola Segata

doi:10.1038/s41591-022-01695-5

Cross-cohort gut microbiome associations with immune checkpoint inhibitor response in advanced melanoma

Karla A. Lee, Andrew Maltez Thomas, Laura A. Bolte, Johannes R. Björk, Laura Kist de Ruijter, Federica Armanini, Francesco Asnicar, Aitor Blanco-Miguez, Ruth Board, Neus Calbet-Llopart, Lisa Derosa, Nathalie Dhomen, Kelly Brooks, Mark Harland, Mark Harries, Emily R. Leeming, Paul Lorigan, Paolo Manghi, Richard Marais, Julia Newton-BishopLuigi Nezi, Federica Pinto, Miriam Potrony, Susana Puig, Patricio Serra-Bellver, Heather M. Shaw, Sabrina Tamburini, Sara Valpione, Amrita Vijay, Levi Waldron, Laurence Zitvogel, Moreno Zolfo, Elisabeth G.E. de Vries, Paul Nathan, Rudolf S.N. Fehrmann, Véronique Bataille, Geke A.P. Hospers, Tim D. Spector^*, Rinse K. Weersma, Nicola Segata

^*Corresponding author for this work

Twin Research & Genetic Epidemiology

Research output: Contribution to journal › Article › peer-review

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Abstract

The composition of the gut microbiome has been associated with clinical responses to immune checkpoint inhibitor (ICI) treatment, but there is limited consensus on the specific microbiome characteristics linked to the clinical benefits of ICIs. We performed shotgun metagenomic sequencing of stool samples collected before ICI initiation from five observational cohorts recruiting ICI-naive patients with advanced cutaneous melanoma (n = 165). Integrating the dataset with 147 metagenomic samples from previously published studies, we found that the gut microbiome has a relevant, but cohort-dependent, association with the response to ICIs. A machine learning analysis confirmed the link between the microbiome and overall response rates (ORRs) and progression-free survival (PFS) with ICIs but also revealed limited reproducibility of microbiome-based signatures across cohorts. Accordingly, a panel of species, including Bifidobacterium pseudocatenulatum, Roseburia spp. and Akkermansia muciniphila, associated with responders was identified, but no single species could be regarded as a fully consistent biomarker across studies. Overall, the role of the human gut microbiome in ICI response appears more complex than previously thought, extending beyond differing microbial species simply present or absent in responders and nonresponders. Future studies should adopt larger sample sizes and take into account the complex interplay of clinical factors with the gut microbiome over the treatment course.

Original language	English
Pages (from-to)	535-544
Number of pages	10
Journal	Nature Medicine
Volume	28
Issue number	3
Early online date	28 Feb 2022
DOIs	https://doi.org/10.1038/s41591-022-01695-5
Publication status	Published - Mar 2022

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Cross-cohort gut microbiome_LEE_Publishedonline28Feb2022_GOLD VoR (CC BY)Final published version, 7.64 MBLicence: CC BY

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Lee, K. A., Thomas, A. M., Bolte, L. A., Björk, J. R., de Ruijter, L. K., Armanini, F., Asnicar, F., Blanco-Miguez, A., Board, R., Calbet-Llopart, N., Derosa, L., Dhomen, N., Brooks, K., Harland, M., Harries, M., Leeming, E. R., Lorigan, P., Manghi, P., Marais, R., ... Segata, N. (2022). Cross-cohort gut microbiome associations with immune checkpoint inhibitor response in advanced melanoma. Nature Medicine, 28(3), 535-544. https://doi.org/10.1038/s41591-022-01695-5

@article{926bb720265d4d0aa39365c5df37d3da,

title = "Cross-cohort gut microbiome associations with immune checkpoint inhibitor response in advanced melanoma",

abstract = "The composition of the gut microbiome has been associated with clinical responses to immune checkpoint inhibitor (ICI) treatment, but there is limited consensus on the specific microbiome characteristics linked to the clinical benefits of ICIs. We performed shotgun metagenomic sequencing of stool samples collected before ICI initiation from five observational cohorts recruiting ICI-naive patients with advanced cutaneous melanoma (n = 165). Integrating the dataset with 147 metagenomic samples from previously published studies, we found that the gut microbiome has a relevant, but cohort-dependent, association with the response to ICIs. A machine learning analysis confirmed the link between the microbiome and overall response rates (ORRs) and progression-free survival (PFS) with ICIs but also revealed limited reproducibility of microbiome-based signatures across cohorts. Accordingly, a panel of species, including Bifidobacterium pseudocatenulatum, Roseburia spp. and Akkermansia muciniphila, associated with responders was identified, but no single species could be regarded as a fully consistent biomarker across studies. Overall, the role of the human gut microbiome in ICI response appears more complex than previously thought, extending beyond differing microbial species simply present or absent in responders and nonresponders. Future studies should adopt larger sample sizes and take into account the complex interplay of clinical factors with the gut microbiome over the treatment course.",

author = "Lee, {Karla A.} and Thomas, {Andrew Maltez} and Bolte, {Laura A.} and Bj{\"o}rk, {Johannes R.} and {de Ruijter}, {Laura Kist} and Federica Armanini and Francesco Asnicar and Aitor Blanco-Miguez and Ruth Board and Neus Calbet-Llopart and Lisa Derosa and Nathalie Dhomen and Kelly Brooks and Mark Harland and Mark Harries and Leeming, {Emily R.} and Paul Lorigan and Paolo Manghi and Richard Marais and Julia Newton-Bishop and Luigi Nezi and Federica Pinto and Miriam Potrony and Susana Puig and Patricio Serra-Bellver and Shaw, {Heather M.} and Sabrina Tamburini and Sara Valpione and Amrita Vijay and Levi Waldron and Laurence Zitvogel and Moreno Zolfo and {de Vries}, {Elisabeth G.E.} and Paul Nathan and Fehrmann, {Rudolf S.N.} and V{\'e}ronique Bataille and Hospers, {Geke A.P.} and Spector, {Tim D.} and Weersma, {Rinse K.} and Nicola Segata",

note = "Funding Information: This work was supported by the Seerave Foundation. The work was also supported by the European Research Council (ERC-STG project MetaPG to N.S.); MIUR {\textquoteleft}Futuro in Ricerca{\textquoteright} (grant RBFR13EWWI_001 to N.S.); the European H2020 program (ONCOBIOME-825410 project and MASTER-818368 project to N.S.); the National Cancer Institute of the National Institutes of Health (grant 1U01CA230551 to N.S. and L.W.); the Premio Internazionale Lombardia e Ricerca 2019 (to N.S.); Spanish Fondo de Investigaciones Sanitarias (grants PI15/00716 and PI15/00956) of the Instituto de Salud Carlos III, Spain, co-financed by European Development Regional Fund “A way to achieve Europe” to ERDF; the Wellcome Trust (grant 100282/Z/12/Z to N.C.-L.); Cancer Research UK (grants A27412 and A22902 to N.C.); and the Dutch Cancer Society (grant 10034 POINTING to E.G.E.d.V.). N.C.-L. is the recipient of a PhD fellowship (FPU17/05453) from Ministerio de Educaci{\'o}n, Cultura y Deportes, Spain. The Leeds group was supported by the Medical Research Council (grant MR/MO19012/1). S.V. was supported by a Harry J. Lloyd Charitable Trust Career Development Award. We acknowledge the Seerave Foundation, which funded this work and many other projects investigating the gut microbiome in human health and disease. We thank the team of the NGS Core Facility at University of Trento for support in sample preparation and for metagenomic sequencing and the high-performance computing team at the University of Trento. We also thank Oncobiome and the Institut Gustave Roussy for their involvement and support of our initiative. The collection of samples from the Hospital Cl{\'i}nic in Barcelona was funded by grant PI15/00716 from Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III, Spain. We would like to thank Ranko Gacesa and the authors of the WindTT_2020 study for kindly providing metagenomic data and metadata for their cohort. Lastly, we would like to thank all the patients who selflessly took the time to collect samples for this project. Funding Information: This work was supported by the Seerave Foundation. The work was also supported by the European Research Council (ERC-STG project MetaPG to N.S.); MIUR ?Futuro in Ricerca? (grant RBFR13EWWI_001 to N.S.); the European H2020 program (ONCOBIOME-825410 project and MASTER-818368 project to N.S.); the National Cancer Institute of the National Institutes of Health (grant 1U01CA230551 to N.S. and L.W.); the Premio Internazionale Lombardia e Ricerca 2019 (to N.S.); Spanish Fondo de Investigaciones Sanitarias (grants PI15/00716 and PI15/00956) of the Instituto de Salud Carlos III, Spain, co-financed by European Development Regional Fund ?A way to achieve Europe? to ERDF; the Wellcome Trust (grant 100282/Z/12/Z to N.C.-L.); Cancer Research UK (grants A27412 and A22902 to N.C.); and the Dutch Cancer Society (grant 10034 POINTING to E.G.E.d.V.). N.C.-L. is the recipient of a PhD fellowship (FPU17/05453) from Ministerio de Educaci?n, Cultura y Deportes, Spain. The Leeds group was supported by the Medical Research Council (grant MR/MO19012/1). S.V. was supported by a Harry J. Lloyd Charitable Trust Career Development Award. We acknowledge the Seerave Foundation, which funded this work and many other projects investigating the gut microbiome in human health and disease. We thank the team of the NGS Core Facility at University of Trento for support in sample preparation and for metagenomic sequencing and the high-performance computing team at the University of Trento. We also thank Oncobiome and the Institut Gustave Roussy for their involvement and support of our initiative. The collection of samples from the Hospital Cl?nic in Barcelona was funded by grant PI15/00716 from Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III, Spain. We would like to thank Ranko Gacesa and the authors of the WindTT_2020 study for kindly providing metagenomic data and metadata for their cohort. Lastly, we would like to thank all the patients who selflessly took the time to collect samples for this project. Funding Information: R.K.W. acted as a consultant for Takeda; received unrestricted research grants from Takeda, Johnson & Johnson, Tramedico and Ferring; and received speaker fees from MSD, AbbVie and Janssen Pharmaceuticals. E.R.L. is a consultant for ZOE Global. E.G.E.d.V. reports an advisory role at Daiichi Sankyo, NSABP and Sanofi (paid to University Medical Center Groningen) and research funding from Amgen, AstraZeneca, Bayer, Chugai Pharma, CytomX Therapeutics, G1 Therapeutics, Genentech, Nordic Nanovector, Radius Health, Regeneron, Roche, Servier and Synthon (paid to University Medical Center Groningen). S.P. received speaker fees from Almirall, BMS, ISDIN, La Roche Posay, Leo Pharma, Regeneron, Roche and Sanofi; acted as advisory board member of Almirall, ISDIN, La Roche Posay, Pfizer, Roche, Regeneron, Sanofi and Sun Pharma; and received research funding from Abbie, AMGEN, ISDIN, La Roche Posay, Leo Pharma and Novartis. R.B. has received honoraria from, and sits on advisory boards of, Novartis, BMS and MSD. All other authors declare no competing interests. Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = mar,

doi = "10.1038/s41591-022-01695-5",

language = "English",

volume = "28",

pages = "535--544",

journal = "Nature Medicine",

issn = "1078-8956",

publisher = "Nature Publishing Group",

number = "3",

}

Lee, KA, Thomas, AM, Bolte, LA, Björk, JR, de Ruijter, LK, Armanini, F, Asnicar, F, Blanco-Miguez, A, Board, R, Calbet-Llopart, N, Derosa, L, Dhomen, N, Brooks, K, Harland, M, Harries, M, Leeming, ER, Lorigan, P, Manghi, P, Marais, R, Newton-Bishop, J, Nezi, L, Pinto, F, Potrony, M, Puig, S, Serra-Bellver, P, Shaw, HM, Tamburini, S, Valpione, S, Vijay, A, Waldron, L, Zitvogel, L, Zolfo, M, de Vries, EGE, Nathan, P, Fehrmann, RSN, Bataille, V, Hospers, GAP, Spector, TD, Weersma, RK & Segata, N 2022, 'Cross-cohort gut microbiome associations with immune checkpoint inhibitor response in advanced melanoma', Nature Medicine, vol. 28, no. 3, pp. 535-544. https://doi.org/10.1038/s41591-022-01695-5

TY - JOUR

T1 - Cross-cohort gut microbiome associations with immune checkpoint inhibitor response in advanced melanoma

AU - Lee, Karla A.

AU - Thomas, Andrew Maltez

AU - Bolte, Laura A.

AU - Björk, Johannes R.

AU - de Ruijter, Laura Kist

AU - Armanini, Federica

AU - Asnicar, Francesco

AU - Blanco-Miguez, Aitor

AU - Board, Ruth

AU - Calbet-Llopart, Neus

AU - Derosa, Lisa

AU - Dhomen, Nathalie

AU - Brooks, Kelly

AU - Harland, Mark

AU - Harries, Mark

AU - Leeming, Emily R.

AU - Lorigan, Paul

AU - Manghi, Paolo

AU - Marais, Richard

AU - Newton-Bishop, Julia

AU - Nezi, Luigi

AU - Pinto, Federica

AU - Potrony, Miriam

AU - Puig, Susana

AU - Serra-Bellver, Patricio

AU - Shaw, Heather M.

AU - Tamburini, Sabrina

AU - Valpione, Sara

AU - Vijay, Amrita

AU - Waldron, Levi

AU - Zitvogel, Laurence

AU - Zolfo, Moreno

AU - de Vries, Elisabeth G.E.

AU - Nathan, Paul

AU - Fehrmann, Rudolf S.N.

AU - Bataille, Véronique

AU - Hospers, Geke A.P.

AU - Spector, Tim D.

AU - Weersma, Rinse K.

AU - Segata, Nicola

N1 - Funding Information: This work was supported by the Seerave Foundation. The work was also supported by the European Research Council (ERC-STG project MetaPG to N.S.); MIUR ‘Futuro in Ricerca’ (grant RBFR13EWWI_001 to N.S.); the European H2020 program (ONCOBIOME-825410 project and MASTER-818368 project to N.S.); the National Cancer Institute of the National Institutes of Health (grant 1U01CA230551 to N.S. and L.W.); the Premio Internazionale Lombardia e Ricerca 2019 (to N.S.); Spanish Fondo de Investigaciones Sanitarias (grants PI15/00716 and PI15/00956) of the Instituto de Salud Carlos III, Spain, co-financed by European Development Regional Fund “A way to achieve Europe” to ERDF; the Wellcome Trust (grant 100282/Z/12/Z to N.C.-L.); Cancer Research UK (grants A27412 and A22902 to N.C.); and the Dutch Cancer Society (grant 10034 POINTING to E.G.E.d.V.). N.C.-L. is the recipient of a PhD fellowship (FPU17/05453) from Ministerio de Educación, Cultura y Deportes, Spain. The Leeds group was supported by the Medical Research Council (grant MR/MO19012/1). S.V. was supported by a Harry J. Lloyd Charitable Trust Career Development Award. We acknowledge the Seerave Foundation, which funded this work and many other projects investigating the gut microbiome in human health and disease. We thank the team of the NGS Core Facility at University of Trento for support in sample preparation and for metagenomic sequencing and the high-performance computing team at the University of Trento. We also thank Oncobiome and the Institut Gustave Roussy for their involvement and support of our initiative. The collection of samples from the Hospital Clínic in Barcelona was funded by grant PI15/00716 from Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III, Spain. We would like to thank Ranko Gacesa and the authors of the WindTT_2020 study for kindly providing metagenomic data and metadata for their cohort. Lastly, we would like to thank all the patients who selflessly took the time to collect samples for this project. Funding Information: This work was supported by the Seerave Foundation. The work was also supported by the European Research Council (ERC-STG project MetaPG to N.S.); MIUR ?Futuro in Ricerca? (grant RBFR13EWWI_001 to N.S.); the European H2020 program (ONCOBIOME-825410 project and MASTER-818368 project to N.S.); the National Cancer Institute of the National Institutes of Health (grant 1U01CA230551 to N.S. and L.W.); the Premio Internazionale Lombardia e Ricerca 2019 (to N.S.); Spanish Fondo de Investigaciones Sanitarias (grants PI15/00716 and PI15/00956) of the Instituto de Salud Carlos III, Spain, co-financed by European Development Regional Fund ?A way to achieve Europe? to ERDF; the Wellcome Trust (grant 100282/Z/12/Z to N.C.-L.); Cancer Research UK (grants A27412 and A22902 to N.C.); and the Dutch Cancer Society (grant 10034 POINTING to E.G.E.d.V.). N.C.-L. is the recipient of a PhD fellowship (FPU17/05453) from Ministerio de Educaci?n, Cultura y Deportes, Spain. The Leeds group was supported by the Medical Research Council (grant MR/MO19012/1). S.V. was supported by a Harry J. Lloyd Charitable Trust Career Development Award. We acknowledge the Seerave Foundation, which funded this work and many other projects investigating the gut microbiome in human health and disease. We thank the team of the NGS Core Facility at University of Trento for support in sample preparation and for metagenomic sequencing and the high-performance computing team at the University of Trento. We also thank Oncobiome and the Institut Gustave Roussy for their involvement and support of our initiative. The collection of samples from the Hospital Cl?nic in Barcelona was funded by grant PI15/00716 from Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III, Spain. We would like to thank Ranko Gacesa and the authors of the WindTT_2020 study for kindly providing metagenomic data and metadata for their cohort. Lastly, we would like to thank all the patients who selflessly took the time to collect samples for this project. Funding Information: R.K.W. acted as a consultant for Takeda; received unrestricted research grants from Takeda, Johnson & Johnson, Tramedico and Ferring; and received speaker fees from MSD, AbbVie and Janssen Pharmaceuticals. E.R.L. is a consultant for ZOE Global. E.G.E.d.V. reports an advisory role at Daiichi Sankyo, NSABP and Sanofi (paid to University Medical Center Groningen) and research funding from Amgen, AstraZeneca, Bayer, Chugai Pharma, CytomX Therapeutics, G1 Therapeutics, Genentech, Nordic Nanovector, Radius Health, Regeneron, Roche, Servier and Synthon (paid to University Medical Center Groningen). S.P. received speaker fees from Almirall, BMS, ISDIN, La Roche Posay, Leo Pharma, Regeneron, Roche and Sanofi; acted as advisory board member of Almirall, ISDIN, La Roche Posay, Pfizer, Roche, Regeneron, Sanofi and Sun Pharma; and received research funding from Abbie, AMGEN, ISDIN, La Roche Posay, Leo Pharma and Novartis. R.B. has received honoraria from, and sits on advisory boards of, Novartis, BMS and MSD. All other authors declare no competing interests. Publisher Copyright: © 2022, The Author(s).

PY - 2022/3

Y1 - 2022/3

N2 - The composition of the gut microbiome has been associated with clinical responses to immune checkpoint inhibitor (ICI) treatment, but there is limited consensus on the specific microbiome characteristics linked to the clinical benefits of ICIs. We performed shotgun metagenomic sequencing of stool samples collected before ICI initiation from five observational cohorts recruiting ICI-naive patients with advanced cutaneous melanoma (n = 165). Integrating the dataset with 147 metagenomic samples from previously published studies, we found that the gut microbiome has a relevant, but cohort-dependent, association with the response to ICIs. A machine learning analysis confirmed the link between the microbiome and overall response rates (ORRs) and progression-free survival (PFS) with ICIs but also revealed limited reproducibility of microbiome-based signatures across cohorts. Accordingly, a panel of species, including Bifidobacterium pseudocatenulatum, Roseburia spp. and Akkermansia muciniphila, associated with responders was identified, but no single species could be regarded as a fully consistent biomarker across studies. Overall, the role of the human gut microbiome in ICI response appears more complex than previously thought, extending beyond differing microbial species simply present or absent in responders and nonresponders. Future studies should adopt larger sample sizes and take into account the complex interplay of clinical factors with the gut microbiome over the treatment course.

AB - The composition of the gut microbiome has been associated with clinical responses to immune checkpoint inhibitor (ICI) treatment, but there is limited consensus on the specific microbiome characteristics linked to the clinical benefits of ICIs. We performed shotgun metagenomic sequencing of stool samples collected before ICI initiation from five observational cohorts recruiting ICI-naive patients with advanced cutaneous melanoma (n = 165). Integrating the dataset with 147 metagenomic samples from previously published studies, we found that the gut microbiome has a relevant, but cohort-dependent, association with the response to ICIs. A machine learning analysis confirmed the link between the microbiome and overall response rates (ORRs) and progression-free survival (PFS) with ICIs but also revealed limited reproducibility of microbiome-based signatures across cohorts. Accordingly, a panel of species, including Bifidobacterium pseudocatenulatum, Roseburia spp. and Akkermansia muciniphila, associated with responders was identified, but no single species could be regarded as a fully consistent biomarker across studies. Overall, the role of the human gut microbiome in ICI response appears more complex than previously thought, extending beyond differing microbial species simply present or absent in responders and nonresponders. Future studies should adopt larger sample sizes and take into account the complex interplay of clinical factors with the gut microbiome over the treatment course.

UR - http://www.scopus.com/inward/record.url?scp=85125299112&partnerID=8YFLogxK

U2 - 10.1038/s41591-022-01695-5

DO - 10.1038/s41591-022-01695-5

M3 - Article

AN - SCOPUS:85125299112

SN - 1078-8956

VL - 28

SP - 535

EP - 544

JO - Nature Medicine

JF - Nature Medicine

IS - 3

ER -

Cross-cohort gut microbiome associations with immune checkpoint inhibitor response in advanced melanoma

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