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

Simon Wabitsch; Justin D McCallen; Olena Kamenyeva; Benjamin Ruf; John C McVey; Juraj Kabat; Juliane S Walz; Yaron Rotman; Kylynda C Bauer; Amanda J Craig; Marie Pouzolles; Ira Phadke; Vanessa Catania; Benjamin L Green; Claude Fu; Laurence P Diggs; Bernd Heinrich; Xin Wei Wang; Chi Ma; Tim F Greten

doi:10.1016/j.jhep.2022.03.010

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

J Hepatol. 2022 Sep;77(3):748-760. doi: 10.1016/j.jhep.2022.03.010. Epub 2022 Apr 1.

Authors

Simon Wabitsch¹, Justin D McCallen¹, Olena Kamenyeva², Benjamin Ruf¹, John C McVey¹, Juraj Kabat², Juliane S Walz¹, Yaron Rotman³, Kylynda C Bauer¹, Amanda J Craig⁴, Marie Pouzolles⁵, Ira Phadke⁵, Vanessa Catania¹, Benjamin L Green¹, Claude Fu¹, Laurence P Diggs¹, Bernd Heinrich¹, Xin Wei Wang⁶, Chi Ma¹, Tim F Greten⁷

Affiliations

¹ Gastrointestinal Malignancy Section, Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
² Biological Imaging Section, Research Technology Branch, National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA.
³ Liver and Energy Metabolism Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
⁴ Laboratory of Human Carcinogenesis, Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
⁵ Basic to Translation Section, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
⁶ 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.
⁷ 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. Electronic address: Tim.greten@nih.gov.

Abstract

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.

Keywords: Hepatic intravital imaging; Hepatic transcriptomics; Immunometabolism; Liver cancer; Metabolic syndrome; NASH immunology.

Published by Elsevier B.V.

Publication types

Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
CD8-Positive T-Lymphocytes / metabolism
Carcinoma, Hepatocellular* / metabolism
Immune Checkpoint Inhibitors / pharmacology
Immune Checkpoint Inhibitors / therapeutic use
Liver / pathology
Liver Neoplasms* / etiology
Metformin* / pharmacology
Metformin* / therapeutic use
Mice
Mice, Inbred C57BL
Non-alcoholic Fatty Liver Disease* / metabolism

Substances

Immune Checkpoint Inhibitors
Metformin

Abstract

Publication types

MeSH terms

Substances

Grants and funding