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Metformin treatment rescues CD8+ T-cell response to immune checkpoint inhibitor therapy in mice with NAFLD

  • Simon Wabitsch
    Affiliations
    Gastrointestinal Malignancy Section, Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
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  • Justin D. McCallen
    Affiliations
    Gastrointestinal Malignancy Section, Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
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  • Olena Kamenyeva
    Affiliations
    Biological Imaging Section, Research Technology Branch, National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA
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  • Benjamin Ruf
    Affiliations
    Gastrointestinal Malignancy Section, Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
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  • John C. McVey
    Affiliations
    Gastrointestinal Malignancy Section, Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
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  • Juraj Kabat
    Affiliations
    Biological Imaging Section, Research Technology Branch, National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA
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  • Author Footnotes
    † Current address: Institute for Cell Biology, Department of Immunology, University of Tübingen, Tübingen, Germany.
    Juliane S. Walz
    Footnotes
    † Current address: Institute for Cell Biology, Department of Immunology, University of Tübingen, Tübingen, Germany.
    Affiliations
    Gastrointestinal Malignancy Section, Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
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  • Yaron Rotman
    Affiliations
    Liver and Energy Metabolism Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
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  • Kylynda C. Bauer
    Affiliations
    Gastrointestinal Malignancy Section, Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
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  • Amanda J. Craig
    Affiliations
    Laboratory of Human Carcinogenesis, Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
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  • Marie Pouzolles
    Affiliations
    Basic to Translation Section, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
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  • Ira Phadke
    Affiliations
    Basic to Translation Section, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
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  • Vanessa Catania
    Affiliations
    Gastrointestinal Malignancy Section, Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
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  • Benjamin L. Green
    Affiliations
    Gastrointestinal Malignancy Section, Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
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  • Claude Fu
    Affiliations
    Gastrointestinal Malignancy Section, Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
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  • Laurence P. Diggs
    Affiliations
    Gastrointestinal Malignancy Section, Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
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  • Author Footnotes
    ‡ Current address: Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
    Bernd Heinrich
    Footnotes
    ‡ Current address: Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
    Affiliations
    Gastrointestinal Malignancy Section, Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
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  • Xin Wei Wang
    Affiliations
    Laboratory of Human Carcinogenesis, Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

    NCI CCR Liver Cancer Program, National Institutes of Health, Bethesda, MD, USA
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  • Chi Ma
    Affiliations
    Gastrointestinal Malignancy Section, Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
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  • Tim F. Greten
    Correspondence
    Corresponding author. Address: Thoracic and GI Malignancies Branch, Center for Cancer Research, NCI, Bethesda MD, USA.
    Affiliations
    Gastrointestinal Malignancy Section, Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

    NCI CCR Liver Cancer Program, National Institutes of Health, Bethesda, MD, USA
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  • Author Footnotes
    † Current address: Institute for Cell Biology, Department of Immunology, University of Tübingen, Tübingen, Germany.
    ‡ Current address: Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
Published:March 31, 2022DOI:https://doi.org/10.1016/j.jhep.2022.03.010

      Highlights

      • Multiple murine models of NASH-HCC show CD8+ T-cell-dependent resistance to ICI therapy.
      • Correlative transcriptomic analysis of hepatic CD8+ T cells revealed NASH-induced mitochondrial aberrations.
      • Although hepatic CD8+ T cells are activated in NASH mice, they have impaired motility and mitochondrial fitness.
      • NASH may diminish the efficacy of ICI therapy in patients with HCC.
      • Metformin can salvage ICI therapy and CD8+ T-cell activity in tumour-bearing NASH mice.

      Background & Aims

      Non-alcoholic steatohepatitis (NASH) represents the fastest growing underlying cause of hepatocellular carcinoma (HCC) and has been shown to impact immune effector cell function. The standard of care for the treatment of advanced HCC is immune checkpoint inhibitor (ICI) therapy, yet NASH may negatively affect the efficacy of ICI therapy in HCC. The immunologic mechanisms underlying the impact of NASH on ICI therapy remain unclear.

      Methods

      Herein, using multiple murine NASH models, we analysed the influence of NASH on the CD8+ T-cell-dependent anti-PD-1 responses against liver cancer. We characterised CD8+ T cells’ transcriptomic, functional, and motility changes in mice receiving a normal diet (ND) or a NASH diet.

      Results

      NASH blunted the effect of anti-PD-1 therapy against liver cancers in multiple murine models. NASH caused a proinflammatory phenotypic change of hepatic CD8+ T cells. Transcriptomic analysis revealed changes related to NASH-dependent impairment of hepatic CD8+ T-cell metabolism. In vivo imaging analysis showed reduced motility of intratumoural CD8+ T cells. Metformin treatment rescued the efficacy of anti-PD-1 therapy against liver tumours in NASH.

      Conclusions

      We discovered that CD8+ T-cell metabolism is critically altered in the context of NASH-related liver cancer, impacting the effectiveness of ICI therapy – a finding which has therapeutic implications in patients with NASH-related liver cancer.

      Lay summary

      Non-alcoholic steatohepatitis represents the fastest growing cause of hepatocellular carcinoma. It is also associated with reduced efficacy of immunotherapy, which is the standard of care for advanced hepatocellular carcinoma. Herein, we show that non-alcoholic steatohepatitis is associated with impaired motility, metabolic function, and response to anti-PD-1 treatment in hepatic CD8+ T cells, which can be rescued by metformin treatment.

      Graphical abstract

      Keywords

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