Lin, Fukuoka, and Koyama et al. focused on how gut microbiota influence the clinical efficacy of ICB. A newly identified bacterial strain named YB328 (genus hominenteromicrobium), was significantly elevated in feces of patients who responded to PD-1 inhibition. Mechanistically, YB328 promoted antitumor efficacy by activating tumor-specific CD103+CD11b- conventional DCs in the gut via multiple TLRs, promoting their migration and in situ activation of a broader repertoire of PD1+CD8+ T cells in the dLNs and TME. YB328 enhanced ICB efficacy in multiple tumor models, and levels correlated with PFS in various cancer types.
Contributed by Katherine Turner
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.
Author Info: (1) Division of Cancer Immunology, National Cancer Center Research Institute, Tokyo, Japan. Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Author Info: (1) Division of Cancer Immunology, National Cancer Center Research Institute, Tokyo, Japan. Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Japan. (2) Division of Cancer Immunology, National Cancer Center Research Institute, Tokyo, Japan. (3) Division of Cancer Immunology, National Cancer Center Research Institute, Tokyo, Japan. 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) Department of Infection Metagenomics, Genome Information Research Center, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan. (8) Department of Infection Metagenomics, Genome Information Research Center, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan. (9) Molecular Biosystems Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Ibaraki, Japan. (10) Biomanufacturing Process Research Center, National Institute of Advanced Industrial Science and Technology (AIST), Ibaraki, Japan. (11) Division of Cancer Immunology, National Cancer Center Research Institute, Tokyo, Japan. (12) Division of Cancer Immunology, National Cancer Center Research Institute, Tokyo, Japan. Department of Thoracic Oncology, National Cancer Center Hospital East, Chiba, Japan. (13) Division of Cancer Immunology, National Cancer Center Research Institute, Tokyo, Japan. Division of Cellular Signaling, National Cancer Center Research Institute, Tokyo, Japan. (14) Division of Cancer Immunology, National Cancer Center Research Institute, Tokyo, Japan. (15) Division of Cancer Immunology, National Cancer Center Research Institute, Tokyo, Japan. (16) Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Japan. (17) Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Japan. (18) Department of Anatomy and Molecular Cell Biology, Nagoya University Graduate School of Medicine, Nagoya, Japan. (19) Department of Anatomy and Molecular Cell Biology, Nagoya University Graduate School of Medicine, Nagoya, Japan. (20) Department of Anatomy and Molecular Cell Biology, Nagoya University Graduate School of Medicine, Nagoya, Japan. (21) Division of Cancer Immunology, National Cancer Center Research Institute, Tokyo, Japan. (22) Division of Cancer Immunology, National Cancer Center Research Institute, Tokyo, Japan. (23) Department of Head and Neck Medical Oncology, National Cancer Center Hospital East, Chiba, Japan. (24) Department of Head and Neck Medical Oncology, National Cancer Center Hospital East, Chiba, Japan. (25) Division of Translational Informatics, Exploratory Oncology Research and Clinical Trial Center (EPOC), National Cancer Center, Chiba, Japan. (26) Department of Head and Neck Medical Oncology, National Cancer Center Hospital East, Chiba, Japan. Translational Research Support Office, National Cancer Center Hospital East, Chiba, Japan. (27) Department of Head and Neck Oncology and Innovative Treatment, Graduate School of Medicine, Kyoto University, Kyoto, Japan. (28) Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Chiba, Japan. (29) Department of Thoracic Oncology, National Cancer Center Hospital East, Chiba, Japan. (30) Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Chiba, Japan. (31) Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Chiba, Japan. (32) Division of Cellular Signaling, National Cancer Center Research Institute, Tokyo, Japan. (33) Molecular Biosystems Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Ibaraki, Japan. (34) Department of Infection Metagenomics, Genome Information Research Center, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan. (35) Benno Laboratory, RIKEN Baton Zone Program, RIKEN Cluster for Science Technology and Innovation Laboratory, Saitama, Japan. benno828@bigm.or.jp. Benno Institute for Gut Microflora (BIGM), Saitama Industrial Technology Center, Saitama, Japan. benno828@bigm.or.jp. (36) Division of Cancer Immunology, National Cancer Center Research Institute, Tokyo, Japan. hnishika@ncc.go.jp. Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Japan. hnishika@ncc.go.jp. Division of Cancer Immune Multicellular System Regulation, Center for Cancer Immunotherapy and Immunobiology, Kyoto University Graduate School of Medicine, Kyoto, Japan. hnishika@ncc.go.jp. Kindai University Faculty of Medicine, Osaka, Japan. hnishika@ncc.go.jp.
