Bifidobacterium bifidum strains synergize with immune checkpoint inhibitors to reduce tumour burden in mice

Se Hoon Lee; Sung Yup Cho; Youngmin Yoon; Changho Park; Jinyoung Sohn; Jin Ju Jeong; Bu Nam Jeon; Mongjoo Jang; Choa An; Suro Lee; Yun Yeon Kim; Gihyeon Kim; Sujeong Kim; Yunjae Kim; Gwang Bin Lee; Eun Ju Lee; Sang Gyun Kim; Hong Sook Kim; Yeongmin Kim; Hyun Kim; Hyun Suk Yang; Sarang Kim; Seonggon Kim; Hayung Chung; Myeong Hee Moon; Myung Hee Nam; Jee Young Kwon; Sungho Won; Joon Suk Park; George M. Weinstock; Charles Lee; Kyoung Wan Yoon; Hansoo Park

doi:10.1038/s41564-020-00831-6

Bifidobacterium bifidum strains synergize with immune checkpoint inhibitors to reduce tumour burden in mice

Se Hoon Lee, Sung Yup Cho, Youngmin Yoon, Changho Park, Jinyoung Sohn, Jin Ju Jeong, Bu Nam Jeon, Mongjoo Jang, Choa An, Suro Lee, Yun Yeon Kim, Gihyeon Kim, Sujeong Kim, Yunjae Kim, Gwang Bin Lee, Eun Ju Lee, Sang Gyun Kim, Hong Sook Kim, Yeongmin Kim, Hyun KimHyun Suk Yang, Sarang Kim, Seonggon Kim, Hayung Chung, Myeong Hee Moon, Myung Hee Nam, Jee Young Kwon, Sungho Won, Joon Suk Park, George M. Weinstock, Charles Lee, Kyoung Wan Yoon, Hansoo Park

Department of Chemistry

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

65 Citations (Scopus)

Abstract

The gut microbiome can influence the development of tumours and the efficacy of cancer therapeutics^1–5; however, the multi-omics characteristics of antitumour bacterial strains have not been fully elucidated. In this study, we integrated metagenomics, genomics and transcriptomics of bacteria, and analyses of mouse intestinal transcriptome and serum metabolome data to reveal an additional mechanism by which bacteria determine the efficacy of cancer therapeutics. In gut microbiome analyses of 96 samples from patients with non-small-cell lung cancer, Bifidobacterium bifidum was abundant in patients responsive to therapy. However, when we treated syngeneic mouse tumours with commercial strains of B. bifidum to establish relevance for potential therapeutic uses, only specific B. bifidum strains reduced tumour burden synergistically with PD-1 blockade or oxaliplatin treatment by eliciting an antitumour host immune response. In mice, these strains induced tuning of the immunological background by potentiating the production of interferon-γ, probably through the enhanced biosynthesis of immune-stimulating molecules and metabolites.

Original language	English
Pages (from-to)	277-288
Number of pages	12
Journal	Nature microbiology
Volume	6
Issue number	3
DOIs	https://doi.org/10.1038/s41564-020-00831-6
Publication status	Published - 2021 Mar

Bibliographical note

Funding Information:
This research was supported by the Bio & Medical Technology Development Program of the National Research Foundation (NRF), funded by the Ministry of Science & ICT (NRF-2017M3A9F3046536 to H.P.); a GIST Research Institute (GRI) grant, funded by the GIST in 2020; Genome and Company (grant number GNC GR 17-01 to H.P.). This work was also supported by grants from National Cancer Centre, Korea (NCC-1911267 to H.P); the Post-Genome Technology Development Program (10067758, Business model development driven by clinico-genomic database for precision immuno-oncology to S.-H.L.) funded by the Ministry of Trade, Industry and Energy (MOTIE, Korea). S.-Y.C. is supported by the Bio & Medical Technology Development Program of the NRF, funded by the Ministry of Science & ICT (NRF-2018M3A9F3056902). This research was also supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number HI17C1076 to K.W.Y). This work was supported by the NRF grant funded by the Korea government (MSIT) (number 2017R1C1B2011196 to K.W.Y). M.H.M. is supported by grant NRF-2018R1A2A1A05019794 from the NRF of Korea. B.-N.J. is supported by the Basic Science Research Program through the NRF of Korea, funded by the Ministry of Education, Science and Technology (MEST) (2018R1C1B6005768). The International Research & Development Program of the NRF of Korea, funded by the Ministry of Science, ICT & Future Planning (grant no. 2015K1A4A3047851) also funded C.L. The Ewha Womans University Professorship is supported in part by the Ewha Womans University research grant of 2017-2019. This study is also supported in part by operational funds from The First Affiliated Hospital of Xi’an Jiaotong University.

Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature Limited.

All Science Journal Classification (ASJC) codes

Microbiology
Immunology
Applied Microbiology and Biotechnology
Genetics
Microbiology (medical)
Cell Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/s41564-020-00831-6

Cite this

Lee, S. H., Cho, S. Y., Yoon, Y., Park, C., Sohn, J., Jeong, J. J., Jeon, B. N., Jang, M., An, C., Lee, S., Kim, Y. Y., Kim, G., Kim, S., Kim, Y., Lee, G. B., Lee, E. J., Kim, S. G., Kim, H. S., Kim, Y., ... Park, H. (2021). Bifidobacterium bifidum strains synergize with immune checkpoint inhibitors to reduce tumour burden in mice. Nature microbiology, 6(3), 277-288. https://doi.org/10.1038/s41564-020-00831-6

@article{05cec60f53ba494da15b4bf5bef32adf,

title = "Bifidobacterium bifidum strains synergize with immune checkpoint inhibitors to reduce tumour burden in mice",

abstract = "The gut microbiome can influence the development of tumours and the efficacy of cancer therapeutics1–5; however, the multi-omics characteristics of antitumour bacterial strains have not been fully elucidated. In this study, we integrated metagenomics, genomics and transcriptomics of bacteria, and analyses of mouse intestinal transcriptome and serum metabolome data to reveal an additional mechanism by which bacteria determine the efficacy of cancer therapeutics. In gut microbiome analyses of 96 samples from patients with non-small-cell lung cancer, Bifidobacterium bifidum was abundant in patients responsive to therapy. However, when we treated syngeneic mouse tumours with commercial strains of B. bifidum to establish relevance for potential therapeutic uses, only specific B. bifidum strains reduced tumour burden synergistically with PD-1 blockade or oxaliplatin treatment by eliciting an antitumour host immune response. In mice, these strains induced tuning of the immunological background by potentiating the production of interferon-γ, probably through the enhanced biosynthesis of immune-stimulating molecules and metabolites.",

author = "Lee, {Se Hoon} and Cho, {Sung Yup} and Youngmin Yoon and Changho Park and Jinyoung Sohn and Jeong, {Jin Ju} and Jeon, {Bu Nam} and Mongjoo Jang and Choa An and Suro Lee and Kim, {Yun Yeon} and Gihyeon Kim and Sujeong Kim and Yunjae Kim and Lee, {Gwang Bin} and Lee, {Eun Ju} and Kim, {Sang Gyun} and Kim, {Hong Sook} and Yeongmin Kim and Hyun Kim and Yang, {Hyun Suk} and Sarang Kim and Seonggon Kim and Hayung Chung and Moon, {Myeong Hee} and Nam, {Myung Hee} and Kwon, {Jee Young} and Sungho Won and Park, {Joon Suk} and Weinstock, {George M.} and Charles Lee and Yoon, {Kyoung Wan} and Hansoo Park",

note = "Funding Information: This research was supported by the Bio & Medical Technology Development Program of the National Research Foundation (NRF), funded by the Ministry of Science & ICT (NRF-2017M3A9F3046536 to H.P.); a GIST Research Institute (GRI) grant, funded by the GIST in 2020; Genome and Company (grant number GNC GR 17-01 to H.P.). This work was also supported by grants from National Cancer Centre, Korea (NCC-1911267 to H.P); the Post-Genome Technology Development Program (10067758, Business model development driven by clinico-genomic database for precision immuno-oncology to S.-H.L.) funded by the Ministry of Trade, Industry and Energy (MOTIE, Korea). S.-Y.C. is supported by the Bio & Medical Technology Development Program of the NRF, funded by the Ministry of Science & ICT (NRF-2018M3A9F3056902). This research was also supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number HI17C1076 to K.W.Y). This work was supported by the NRF grant funded by the Korea government (MSIT) (number 2017R1C1B2011196 to K.W.Y). M.H.M. is supported by grant NRF-2018R1A2A1A05019794 from the NRF of Korea. B.-N.J. is supported by the Basic Science Research Program through the NRF of Korea, funded by the Ministry of Education, Science and Technology (MEST) (2018R1C1B6005768). The International Research & Development Program of the NRF of Korea, funded by the Ministry of Science, ICT & Future Planning (grant no. 2015K1A4A3047851) also funded C.L. The Ewha Womans University Professorship is supported in part by the Ewha Womans University research grant of 2017-2019. This study is also supported in part by operational funds from The First Affiliated Hospital of Xi{\textquoteright}an Jiaotong University. Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to Springer Nature Limited.",

year = "2021",

month = mar,

doi = "10.1038/s41564-020-00831-6",

language = "English",

volume = "6",

pages = "277--288",

journal = "Nature Microbiology",

issn = "2058-5276",

publisher = "Nature Publishing Group",

number = "3",

}

Lee, SH, Cho, SY, Yoon, Y, Park, C, Sohn, J, Jeong, JJ, Jeon, BN, Jang, M, An, C, Lee, S, Kim, YY, Kim, G, Kim, S, Kim, Y, Lee, GB, Lee, EJ, Kim, SG, Kim, HS, Kim, Y, Kim, H, Yang, HS, Kim, S, Kim, S, Chung, H, Moon, MH, Nam, MH, Kwon, JY, Won, S, Park, JS, Weinstock, GM, Lee, C, Yoon, KW & Park, H 2021, 'Bifidobacterium bifidum strains synergize with immune checkpoint inhibitors to reduce tumour burden in mice', Nature microbiology, vol. 6, no. 3, pp. 277-288. https://doi.org/10.1038/s41564-020-00831-6

TY - JOUR

T1 - Bifidobacterium bifidum strains synergize with immune checkpoint inhibitors to reduce tumour burden in mice

AU - Lee, Se Hoon

AU - Cho, Sung Yup

AU - Yoon, Youngmin

AU - Park, Changho

AU - Sohn, Jinyoung

AU - Jeong, Jin Ju

AU - Jeon, Bu Nam

AU - Jang, Mongjoo

AU - An, Choa

AU - Lee, Suro

AU - Kim, Yun Yeon

AU - Kim, Gihyeon

AU - Kim, Sujeong

AU - Kim, Yunjae

AU - Lee, Gwang Bin

AU - Lee, Eun Ju

AU - Kim, Sang Gyun

AU - Kim, Hong Sook

AU - Kim, Yeongmin

AU - Kim, Hyun

AU - Yang, Hyun Suk

AU - Kim, Sarang

AU - Kim, Seonggon

AU - Chung, Hayung

AU - Moon, Myeong Hee

AU - Nam, Myung Hee

AU - Kwon, Jee Young

AU - Won, Sungho

AU - Park, Joon Suk

AU - Weinstock, George M.

AU - Lee, Charles

AU - Yoon, Kyoung Wan

AU - Park, Hansoo

N1 - Funding Information: This research was supported by the Bio & Medical Technology Development Program of the National Research Foundation (NRF), funded by the Ministry of Science & ICT (NRF-2017M3A9F3046536 to H.P.); a GIST Research Institute (GRI) grant, funded by the GIST in 2020; Genome and Company (grant number GNC GR 17-01 to H.P.). This work was also supported by grants from National Cancer Centre, Korea (NCC-1911267 to H.P); the Post-Genome Technology Development Program (10067758, Business model development driven by clinico-genomic database for precision immuno-oncology to S.-H.L.) funded by the Ministry of Trade, Industry and Energy (MOTIE, Korea). S.-Y.C. is supported by the Bio & Medical Technology Development Program of the NRF, funded by the Ministry of Science & ICT (NRF-2018M3A9F3056902). This research was also supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number HI17C1076 to K.W.Y). This work was supported by the NRF grant funded by the Korea government (MSIT) (number 2017R1C1B2011196 to K.W.Y). M.H.M. is supported by grant NRF-2018R1A2A1A05019794 from the NRF of Korea. B.-N.J. is supported by the Basic Science Research Program through the NRF of Korea, funded by the Ministry of Education, Science and Technology (MEST) (2018R1C1B6005768). The International Research & Development Program of the NRF of Korea, funded by the Ministry of Science, ICT & Future Planning (grant no. 2015K1A4A3047851) also funded C.L. The Ewha Womans University Professorship is supported in part by the Ewha Womans University research grant of 2017-2019. This study is also supported in part by operational funds from The First Affiliated Hospital of Xi’an Jiaotong University. Publisher Copyright: © 2021, The Author(s), under exclusive licence to Springer Nature Limited.

PY - 2021/3

Y1 - 2021/3

N2 - The gut microbiome can influence the development of tumours and the efficacy of cancer therapeutics1–5; however, the multi-omics characteristics of antitumour bacterial strains have not been fully elucidated. In this study, we integrated metagenomics, genomics and transcriptomics of bacteria, and analyses of mouse intestinal transcriptome and serum metabolome data to reveal an additional mechanism by which bacteria determine the efficacy of cancer therapeutics. In gut microbiome analyses of 96 samples from patients with non-small-cell lung cancer, Bifidobacterium bifidum was abundant in patients responsive to therapy. However, when we treated syngeneic mouse tumours with commercial strains of B. bifidum to establish relevance for potential therapeutic uses, only specific B. bifidum strains reduced tumour burden synergistically with PD-1 blockade or oxaliplatin treatment by eliciting an antitumour host immune response. In mice, these strains induced tuning of the immunological background by potentiating the production of interferon-γ, probably through the enhanced biosynthesis of immune-stimulating molecules and metabolites.

AB - The gut microbiome can influence the development of tumours and the efficacy of cancer therapeutics1–5; however, the multi-omics characteristics of antitumour bacterial strains have not been fully elucidated. In this study, we integrated metagenomics, genomics and transcriptomics of bacteria, and analyses of mouse intestinal transcriptome and serum metabolome data to reveal an additional mechanism by which bacteria determine the efficacy of cancer therapeutics. In gut microbiome analyses of 96 samples from patients with non-small-cell lung cancer, Bifidobacterium bifidum was abundant in patients responsive to therapy. However, when we treated syngeneic mouse tumours with commercial strains of B. bifidum to establish relevance for potential therapeutic uses, only specific B. bifidum strains reduced tumour burden synergistically with PD-1 blockade or oxaliplatin treatment by eliciting an antitumour host immune response. In mice, these strains induced tuning of the immunological background by potentiating the production of interferon-γ, probably through the enhanced biosynthesis of immune-stimulating molecules and metabolites.

UR - http://www.scopus.com/inward/record.url?scp=85099102094&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85099102094&partnerID=8YFLogxK

U2 - 10.1038/s41564-020-00831-6

DO - 10.1038/s41564-020-00831-6

M3 - Article

C2 - 33432149

AN - SCOPUS:85099102094

SN - 2058-5276

VL - 6

SP - 277

EP - 288

JO - Nature Microbiology

JF - Nature Microbiology

IS - 3

ER -

Bifidobacterium bifidum strains synergize with immune checkpoint inhibitors to reduce tumour burden in mice

Abstract

Bibliographical note

All Science Journal Classification (ASJC) codes

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this