Microbiota-driven antitumour immunity mediated by dendritic cell migration

doi:10.1038/s41586-025-09249-8

. 2025 Jul 14.

doi: 10.1038/s41586-025-09249-8. Online ahead of print.

Microbiota-driven antitumour immunity mediated by dendritic cell migration

Nina Yi-Tzu Lin^#^{1

2}, Shota Fukuoka^#¹, Shohei Koyama^#^{1

3}, Daisuke Motooka⁴, Dieter M Tourlousse⁵, Yuko Shigeno⁶, Yuki Matsumoto⁴, Hiroyuki Yamano⁴, Kazutoshi Murotomi⁵, Hideyuki Tamaki⁷, Takuma Irie¹, Eri Sugiyama^{1

8}, Shogo Kumagai^{1

9}, Kota Itahashi¹, Tokiyoshi Tanegashima¹, Kaori Fujimaki², Sachiko Ito², Mariko Shindo¹⁰, Takahiro Tsuji¹⁰, Hiroaki Wake¹⁰, Keisuke Watanabe¹, Yuka Maeda¹, Tomohiro Enokida¹¹, Makoto Tahara¹¹, Riu Yamashita¹², Takao Fujisawa^{11

13}, Motoo Nomura¹⁴, Akihito Kawazoe¹⁵, Koichi Goto⁸, Toshihiko Doi¹⁵, Kohei Shitara¹⁵, Hiroyuki Mano⁹, Yuji Sekiguchi⁵, Shota Nakamura⁴, Yoshimi Benno^{16

17}, Hiroyoshi Nishikawa^{18

19

20

21}

Affiliations

¹ Division of Cancer Immunology, National Cancer Center Research Institute, Tokyo, Japan.
² Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
³ Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Osaka, Japan.
⁴ Department of Infection Metagenomics, Genome Information Research Center, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.
⁵ Molecular Biosystems Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Ibaraki, Japan.
⁶ Benno Laboratory, RIKEN Baton Zone Program, RIKEN Cluster for Science Technology and Innovation Laboratory, Saitama, Japan.
⁷ Biomanufacturing Process Research Center, National Institute of Advanced Industrial Science and Technology (AIST), Ibaraki, Japan.
⁸ Department of Thoracic Oncology, National Cancer Center Hospital East, Chiba, Japan.
⁹ Division of Cellular Signaling, National Cancer Center Research Institute, Tokyo, Japan.
¹⁰ Department of Anatomy and Molecular Cell Biology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
¹¹ Department of Head and Neck Medical Oncology, National Cancer Center Hospital East, Chiba, Japan.
¹² Division of Translational Informatics, Exploratory Oncology Research and Clinical Trial Center (EPOC), National Cancer Center, Chiba, Japan.
¹³ Translational Research Support Office, National Cancer Center Hospital East, Chiba, Japan.
¹⁴ Department of Head and Neck Oncology and Innovative Treatment, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
¹⁵ Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Chiba, Japan.
¹⁶ Benno Laboratory, RIKEN Baton Zone Program, RIKEN Cluster for Science Technology and Innovation Laboratory, Saitama, Japan. [email protected].
¹⁷ Benno Institute for Gut Microflora (BIGM), Saitama Industrial Technology Center, Saitama, Japan. [email protected].
¹⁸ Division of Cancer Immunology, National Cancer Center Research Institute, Tokyo, Japan. [email protected].
¹⁹ Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Japan. [email protected].
²⁰ Division of Cancer Immune Multicellular System Regulation, Center for Cancer Immunotherapy and Immunobiology, Kyoto University Graduate School of Medicine, Kyoto, Japan. [email protected].
²¹ Kindai University Faculty of Medicine, Osaka, Japan. [email protected].

^# Contributed equally.

PMID: 40659786
DOI: 10.1038/s41586-025-09249-8

Microbiota-driven antitumour immunity mediated by dendritic cell migration

Nina Yi-Tzu Lin et al. Nature. 2025.

. 2025 Jul 14.

doi: 10.1038/s41586-025-09249-8. Online ahead of print.

Authors

Affiliations

¹ Division of Cancer Immunology, National Cancer Center Research Institute, Tokyo, Japan.
² Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
³ Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Osaka, Japan.
⁴ Department of Infection Metagenomics, Genome Information Research Center, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.
⁵ Molecular Biosystems Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Ibaraki, Japan.
⁶ Benno Laboratory, RIKEN Baton Zone Program, RIKEN Cluster for Science Technology and Innovation Laboratory, Saitama, Japan.
⁷ Biomanufacturing Process Research Center, National Institute of Advanced Industrial Science and Technology (AIST), Ibaraki, Japan.
⁸ Department of Thoracic Oncology, National Cancer Center Hospital East, Chiba, Japan.
⁹ Division of Cellular Signaling, National Cancer Center Research Institute, Tokyo, Japan.
¹⁰ Department of Anatomy and Molecular Cell Biology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
¹¹ Department of Head and Neck Medical Oncology, National Cancer Center Hospital East, Chiba, Japan.
¹² Division of Translational Informatics, Exploratory Oncology Research and Clinical Trial Center (EPOC), National Cancer Center, Chiba, Japan.
¹³ Translational Research Support Office, National Cancer Center Hospital East, Chiba, Japan.
¹⁴ Department of Head and Neck Oncology and Innovative Treatment, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
¹⁵ Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Chiba, Japan.
¹⁶ Benno Laboratory, RIKEN Baton Zone Program, RIKEN Cluster for Science Technology and Innovation Laboratory, Saitama, Japan. [email protected].
¹⁷ Benno Institute for Gut Microflora (BIGM), Saitama Industrial Technology Center, Saitama, Japan. [email protected].
¹⁸ Division of Cancer Immunology, National Cancer Center Research Institute, Tokyo, Japan. [email protected].
¹⁹ Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Japan. [email protected].
²⁰ Division of Cancer Immune Multicellular System Regulation, Center for Cancer Immunotherapy and Immunobiology, Kyoto University Graduate School of Medicine, Kyoto, Japan. [email protected].
²¹ Kindai University Faculty of Medicine, Osaka, Japan. [email protected].

^# Contributed equally.

PMID: 40659786
DOI: 10.1038/s41586-025-09249-8

Abstract

Gut microbiota influence the antitumour efficacy of immune checkpoint blockade^1-6, but the mechanisms of action have not been fully elucidated. Here, we show that a new strain of the bacterial genus Hominenteromicrobium (designated YB328) isolated from the faeces of patients who responded to programmed cell death 1 (PD-1) blockade augmented antitumour responses in mice. YB328 activated tumour-specific CD8⁺ T cells through the stimulation of CD103⁺CD11b^- conventional dendritic cells (cDCs), which, following exposure in the gut, migrated to the tumour microenvironment. Mice showed improved antitumour efficacy of PD-1 blockade when treated with faecal transplants from non-responder patients supplemented with YB238. This result suggests that YB328 could function in a dominant manner. YB328-activated CD103⁺CD11b^- cDCs showed prolonged engagement with tumour-specific CD8⁺ T cells and promoted PD-1 expression in these cells. Moreover, YB238-augmented antitumour efficacy of PD-1 blockade treatment was observed in multiple mouse models of cancer. Patients with elevated YB328 abundance had increased infiltration of CD103⁺CD11b^- cDCs in tumours and had a favourable response to PD-1 blockade therapy in various cancer types. We propose that gut microbiota enhance antitumour immunity by accelerating the maturation and migration of CD103⁺CD11b^- cDCs to increase the number of CD8⁺ T cells that respond to diverse tumour antigens.

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Conflict of interest statement

Competing interests: S. Koyama receives research funding from Otsuka Pharmaceutical and Chugai Pharmaceutical outside this study and receives honoraria from MSD and Chugai Pharmaceutical. K.I. receives honoraria from MSD and Chugai Pharmaceutical. M.N. receives honoraria (lecture fees) from MSD, Ono Pharmaceutical and Bristol-Myers Squibb (BMS). A.K. receives personal fees from Daiichi-Sankyo, Lilly, Ono Pharmaceutical, Taiho Pharmaceutical, BMS, Merck Pharmaceutical, Sumitomo Dainippon Pharma and AstraZeneca outside this study. K.W. serves as a board member and a founder of ARC Therapies outside of this study. T.D. receives personal fees for advisory roles from Sumitomo Dainippon Pharma, Taiho Pharmaceutical, Takeda Pharmaceutical, Chugai Pharmaceutical, AbbVie, Bayer, Rakuten Medical, Otsuka Pharmaceutical, KAKEN Pharmaceutical, Kyowa Kirin, SHIONOGI, PRA Health Science, A2 Health Care, Noile-Immune Biotech, MSD, Daiichi-Sankyo, Amgen, Novartis, Boehringer Ingelheim, Janssen Pharmaceutical and Astellas Pharmaceutical; receives honoraria (lecture fees) from BMS, Rakuten Medical, Ono Pharmaceutical, Daiichi-Sankyo and AstraZeneca; and receives research funding from Lilly, MSD, Daiichi-Sankyo, Sumitomo Dainippon Pharma, Taiho Pharmaceutical, Novartis, Merck Pharmaceutical, Janssen Pharmaceutical, Boehringer Ingelheim, Pfizer, BMS, AbbVie, Eisai, IQVIA, Chugai Pharmaceutical and SHIONOGI outside this study. K.S. reports receiving personal fees for consulting and advisory roles from BMS, Takeda, Ono Pharmaceutical, Novartis, Daiichi Sankyo, Amgen, Boehringer Ingelheim, Merck Pharmaceutical, Astellas, Guardant Health Japan, Janssen, AstraZeneca, Zymeworks Biopharmaceuticals, ALX Oncology and Bayer; receiving honoraria from BMS, Ono Pharmaceutical, Janssen, Eli Lilly, Astellas and AstraZeneca; and receiving research funding (all to the institution) from Astellas, Ono Pharmaceutical, Daiichi Sankyo, Taiho Pharmaceutical, Chugai, Merck Pharmaceutical, Amgen, Eisai, PRA Health Sciences and Syneos Health, outside the submitted work. H.M. receives research grants from Ono Pharmaceutical, Daiichi Sankyo, PFDeNA, Konica-Minolta and Ambry Genetics and serves as a board member of CureGene outside this study. H.N. receives research funding and honoraria (lecture fees) from Ono Pharmaceutical, BMS, Chugai Pharmaceutical, BD Japan and MSD; receives honoraria (lecture fees) from Amgen; receives research funding from Taiho Pharmaceutical, Daiichi-Sankyo, Kyowa Kirin, Zenyaku Kogyo, Oncolys BioPharma, Debiopharma, Asahi-Kasei, Sysmex, Fujifilm, SRL, Astellas Pharmaceutical, Sumitomo Dainippon Pharma, ARC Therapies and RIKAKEN Holdings; and serves as a scientific advisor and a founder of ARC Therapies and a scientific advisor of LTZ Therapeutics outside this study. S.F., Y.B. and H.N. are the primary inventors on pending patents 2020-165470 belonging to RIKEN and the National Cancer Center Japan. The other authors declare no competing interests.

References

1. Routy, B. et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science 359, 91–97 (2018). - PubMed
1. Gopalakrishnan, V. et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science 359, 97–103 (2018). - PubMed
1. Matson, V. et al. The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science 359, 104–108 (2018). - PubMed - PMC
1. Sivan, A. et al. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science 350, 1084–1089 (2015). - PubMed - PMC
1. Vetizou, M. et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science 350, 1079–1084 (2015). - PubMed - PMC

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[1] Routy, B. et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science 359, 91–97 (2018). - PubMed

[2] Routy, B. et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science 359, 91–97 (2018). - PubMed

[3] Gopalakrishnan, V. et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science 359, 97–103 (2018). - PubMed

[4] Gopalakrishnan, V. et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science 359, 97–103 (2018). - PubMed

[5] Matson, V. et al. The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science 359, 104–108 (2018). - PubMed - PMC

[6] Matson, V. et al. The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science 359, 104–108 (2018). - PubMed - PMC

[7] Sivan, A. et al. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science 350, 1084–1089 (2015). - PubMed - PMC

[8] Sivan, A. et al. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science 350, 1084–1089 (2015). - PubMed - PMC

[9] Vetizou, M. et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science 350, 1079–1084 (2015). - PubMed - PMC

[10] Vetizou, M. et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science 350, 1079–1084 (2015). - PubMed - PMC

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Microbiota-driven antitumour immunity mediated by dendritic cell migration

Affiliations

Microbiota-driven antitumour immunity mediated by dendritic cell migration

Authors

Affiliations

Abstract

Conflict of interest statement

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