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Cytotoxic T Cells-mediated Immune Response01:27

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A Microbial Lipid-ATP Synthase Axis Fuels NK Cell Antitumor Activity.

Kaiyuan Yu1, Xinyu Sun1, Wanxia Ma1

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Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
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Gut bacteria outer membrane vesicles (OMVs) containing sphingosine (SP) enhance natural killer (NK) cell function, inhibiting tumor growth. This discovery opens avenues for novel microbiota-derived immunotherapies against cancer.

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Area of Science:

  • Microbiome-host interactions
  • Immunology
  • Cancer biology
  • Metabolic pathways

Background:

  • The gut microbiota modulates systemic immunity and cancer development through inter-organ communication.
  • Mechanisms of outer membrane vesicle (OMV)-mediated communication from gut bacteria remain largely undefined.
  • Sphingosine (SP), a bioactive lipid, is found in OMVs.

Purpose of the Study:

  • To investigate the role of Bacteroides intestinalis OMVs in restraining extra-intestinal tumor growth.
  • To elucidate the molecular mechanisms by which microbial OMVs influence immune cell function.
  • To explore the potential of microbiota-derived lipids as immunotherapies.

Main Methods:

  • Analysis of OMVs from Bacteroides intestinalis for lipid content, specifically sphingosine (SP).
  • Investigation of SP binding to the ATP5F1A subunit of mitochondrial ATP synthase in NK cells.
  • Assessment of NK cell function, including mitochondrial efficiency, ROS production, and IFN-γ secretion.
  • Inhibition of murine tumor growth using B. intestinalis OMVs or SP administration, alone and in combination with anti-PD-1 therapy.

Main Results:

  • B. intestinalis OMVs are enriched in sphingosine (SP), which directly binds to ATP5F1A on mitochondrial ATP synthase.
  • This interaction enhances NK cell mitochondrial efficiency, reduces ROS production, and upregulates IFN-γ secretion, boosting cytotoxicity and tumor infiltration.
  • Administration of B. intestinalis OMVs or SP significantly inhibits tumor growth in mice, with enhanced efficacy when combined with anti-PD-1 therapy.

Conclusions:

  • Gut microbial OMVs, specifically those from B. intestinalis enriched in SP, can directly activate NK cells and restrain tumor growth.
  • The microbial lipid-SP-mitochondrial ATP synthase axis represents a novel mechanism for immune modulation.
  • Microbiota-derived lipid-based therapies hold promise for enhancing cancer immunotherapy.