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nature portfolio privacy policy author information authors peer review file bacteria-derived hla-bound peptides advertising code availability common language peer review ethanol solutions supplementary information anti-cancer drug development received research funding reprints nature 569 nature 592 nature 617 nature references gandhi facilitates anti-pd-l1 efficacy interferon-gamma-mediated antitumor response open-label included anti-pd-l1 [e1l3n anti-pd-1 enhanced tumor-infiltrating including patient-derived tumoroids author correspondence original author cancer-related deaths worldwide develop apical/basal polarity institutional research committee kras-mutant lung adenocarcinoma serum deprived dmem/f12 dna/rna mini kit data availability reporting summary cis-pd-l1/cd80 interactions free access identify anti-lta-gold particles proinflammatory cytokine tnf-α35 tlr-4-nf-κb signaling pathway small-cell lung cancer gram-positive commensal bifidobacteria influence pd-l2 expression made critical development support organoid development disposable ultra-pure water typical crypt-villus architecture goat anti-mouse-gold capture high-resolution images stabilizing c-myc mrna

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         headline:Gut commensal Bifidobacterium-derived extracellular vesicles modulate the therapeutic effects of anti-PD-1 in lung cancer
         description:Lung cancer is the leading cause of cancer-related deaths worldwide. Although immunotherapy such as anti-programmed death-1 and its ligand 1 (PD-1/L1) is a standard treatment for advanced non-small cell lung cancer (NSCLC), many patients do not derive benefit directly. Several studies have elucidated new strategies to improve the antitumor immune response through gut microbiota modulation. However, it remains largely debatable regarding how gut microbiota remotely affect lung cancer microenvironment and subsequently modulate immunotherapy response. Here we show that commensal Bifidobacterium-derived extracellular vesicles (Bif.BEVs) can modulate the therapeutic effect of anti-PD-1 therapy in NSCLC. These Bif.BEVs are up-taken by lung cancer cells predominantly via dynamin-dependent endocytosis and upregulate PD-L1 expression through TLR4-NF-κB pathway. They also efficiently penetrate murine intestinal and patient-derived lung cancer organoids. Oral gavage of these Bif.BEVs result in their accumulation in tumors in mice. Using a syngeneic mouse model, Bif.BEVs are found to synergize the anti-tumor effect of anti-PD-1 via modulation of key cytokines, immune response and oncogenic pathways, and increase in tumor-infiltrating CD8+ T cells. Our study therefore identifies a link between Bif.BEVs and the tumor microenvironment, providing an alternative mechanism to explain how gut microbiota can influence immunotherapy response, particularly in tumors located anatomically distant from the gut. The precise mechanism by which gut microbiota influence the immunotherapy response of tumors in anatomically distant locations remains debated. In this study, using organoids and animal models, Zhang and colleagues show that Bifidobacterium-derived extracellular vesicles synergize the anti-tumor effect of anti-PD-1 via modulation of key cytokines, immune response and oncogenic pathways, and increase in tumor-infiltrating CD8 + T cells.
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      description:Lung cancer is the leading cause of cancer-related deaths worldwide. Although immunotherapy such as anti-programmed death-1 and its ligand 1 (PD-1/L1) is a standard treatment for advanced non-small cell lung cancer (NSCLC), many patients do not derive benefit directly. Several studies have elucidated new strategies to improve the antitumor immune response through gut microbiota modulation. However, it remains largely debatable regarding how gut microbiota remotely affect lung cancer microenvironment and subsequently modulate immunotherapy response. Here we show that commensal Bifidobacterium-derived extracellular vesicles (Bif.BEVs) can modulate the therapeutic effect of anti-PD-1 therapy in NSCLC. These Bif.BEVs are up-taken by lung cancer cells predominantly via dynamin-dependent endocytosis and upregulate PD-L1 expression through TLR4-NF-κB pathway. They also efficiently penetrate murine intestinal and patient-derived lung cancer organoids. Oral gavage of these Bif.BEVs result in their accumulation in tumors in mice. Using a syngeneic mouse model, Bif.BEVs are found to synergize the anti-tumor effect of anti-PD-1 via modulation of key cytokines, immune response and oncogenic pathways, and increase in tumor-infiltrating CD8+ T cells. Our study therefore identifies a link between Bif.BEVs and the tumor microenvironment, providing an alternative mechanism to explain how gut microbiota can influence immunotherapy response, particularly in tumors located anatomically distant from the gut. The precise mechanism by which gut microbiota influence the immunotherapy response of tumors in anatomically distant locations remains debated. In this study, using organoids and animal models, Zhang and colleagues show that Bifidobacterium-derived extracellular vesicles synergize the anti-tumor effect of anti-PD-1 via modulation of key cytokines, immune response and oncogenic pathways, and increase in tumor-infiltrating CD8 + T cells.
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            name:University of Kansas Medical Center
            address:
               name:Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, USA
               type:PostalAddress
            type:Organization
      name:Vikalp Vishwakarma
      affiliation:
            name:University of Kansas Medical Center
            address:
               name:Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, USA
               type:PostalAddress
            type:Organization
      name:Caleb Kutz
      affiliation:
            name:University of Kansas Medical Center
            address:
               name:Division of Medical Oncology, Department of Internal Medicine, University of Kansas Medical Center, Kansas City, USA
               type:PostalAddress
            type:Organization
      name:Sonali Choudhury
      affiliation:
            name:University of Kansas Comprehensive Cancer Center
            address:
               name:Department of Cancer Biology, University of Kansas Comprehensive Cancer Center, Kansas City, USA
               type:PostalAddress
            type:Organization
      name:Harsh Pathak
      affiliation:
            name:University of Kansas Medical Center
            address:
               name:Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, USA
               type:PostalAddress
            type:Organization
      name:Qun Dai
      affiliation:
            name:University of Kansas Medical Center
            address:
               name:Division of Medical Oncology, Department of Internal Medicine, University of Kansas Medical Center, Kansas City, USA
               type:PostalAddress
            type:Organization
      name:Weijing Sun
      url:http://orcid.org/0000-0001-6549-9605
      affiliation:
            name:University of Kansas Medical Center
            address:
               name:Division of Medical Oncology, Department of Internal Medicine, University of Kansas Medical Center, Kansas City, USA
               type:PostalAddress
            type:Organization
      name:Rashna Madan
      affiliation:
            name:University of Kansas Medical Center
            address:
               name:Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, USA
               type:PostalAddress
            type:Organization
      name:Cuncong Zhong
      affiliation:
            name:University of Kansas
            address:
               name:Department of Electrical Engineering and Computer Science, University of Kansas, Lawrence, USA
               type:PostalAddress
            type:Organization
      name:Mary A. Markiewicz
      url:http://orcid.org/0000-0001-5685-8573
      affiliation:
            name:University of Kansas Medical Center
            address:
               name:Department of Microbiology, Molecular Genetics & Immunology, University of Kansas Medical Center, Kansas City, USA
               type:PostalAddress
            type:Organization
      name:Jun Zhang
      url:http://orcid.org/0000-0001-7886-6187
      affiliation:
            name:University of Kansas Medical Center
            address:
               name:Division of Medical Oncology, Department of Internal Medicine, University of Kansas Medical Center, Kansas City, USA
               type:PostalAddress
            type:Organization
            name:University of Kansas Comprehensive Cancer Center
            address:
               name:Department of Cancer Biology, University of Kansas Comprehensive Cancer Center, Kansas City, USA
               type:PostalAddress
            type:Organization
      email:[email protected]
PostalAddress:
      name:Division of Medical Oncology, Department of Internal Medicine, University of Kansas Medical Center, Kansas City, USA
      name:Division of Medical Oncology, Department of Internal Medicine, University of Kansas Medical Center, Kansas City, USA
      name:Division of Medical Oncology, Department of Internal Medicine, University of Kansas Medical Center, Kansas City, USA
      name:Division of Medical Oncology, Department of Internal Medicine, University of Kansas Medical Center, Kansas City, USA
      name:Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, USA
      name:Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, USA
      name:Division of Medical Oncology, Department of Internal Medicine, University of Kansas Medical Center, Kansas City, USA
      name:Department of Cancer Biology, University of Kansas Comprehensive Cancer Center, Kansas City, USA
      name:Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, USA
      name:Division of Medical Oncology, Department of Internal Medicine, University of Kansas Medical Center, Kansas City, USA
      name:Division of Medical Oncology, Department of Internal Medicine, University of Kansas Medical Center, Kansas City, USA
      name:Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, USA
      name:Department of Electrical Engineering and Computer Science, University of Kansas, Lawrence, USA
      name:Department of Microbiology, Molecular Genetics & Immunology, University of Kansas Medical Center, Kansas City, USA
      name:Division of Medical Oncology, Department of Internal Medicine, University of Kansas Medical Center, Kansas City, USA
      name:Department of Cancer Biology, University of Kansas Comprehensive Cancer Center, Kansas City, USA

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