Anti-CD122 antibody restores specific CD8+ T cell response in nonalcoholic steatohepatitis and prevents hepatocellular carcinoma growth

Article Article scientifique Article Anti-CD122 antibody restores specific CD8+ T cell response in nonalcoholic steatohepatitis and prevents hepatocellular carcinoma growth eng 2023-03-02 2023 author Lacotte Stéphanie 0000-0002-5921-6389 Transplantation and Hepatology Laboratory, Department of Surgery, University of Geneva, Geneva, Switzerland. 714209 Département de chirurgie (CHIRU) author Slits Florence Transplantation and Hepatology Laboratory, Department of Surgery, University of Geneva, Geneva, Switzerland. 782467 Département de chirurgie (CHIRU) author Moeckli Beat 0000-0002-9020-8416 Transplantation and Hepatology Laboratory, Department of Surgery, University of Geneva, Geneva, Switzerland.,Division of Abdominal Surgery, Department of Surgery, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland. 848954 author Peloso Andréa 0000-0002-3089-0230 Transplantation and Hepatology Laboratory, Department of Surgery, University of Geneva, Geneva, Switzerland.,Division of Abdominal Surgery, Department of Surgery, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland. 878393 author Koenig Stéphan Hans 0000-0002-0801-279X Department of Physiology, University of Geneva, Geneva, Switzerland. 66982 author Tihy Matthieu 0000-0002-9314-4657 Division of Clinical Pathology, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland. 914217 author El Hajji Sofia 0000-0002-3028-6148 Transplantation and Hepatology Laboratory, Department of Surgery, University of Geneva, Geneva, Switzerland. 807059 author Gex Quentin Transplantation and Hepatology Laboratory, Department of Surgery, University of Geneva, Geneva, Switzerland. 701133 Département de médecine (DEMED) author Rubbia-Brandt Laura 0000-0002-3173-3376 Division of Clinical Pathology, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland. 31809 Département de pathologie et immunologie (PATIM) author Toso Christian 0000-0003-1652-4522 Transplantation and Hepatology Laboratory, Department of Surgery, University of Geneva, Geneva, Switzerland.,Division of Abdominal Surgery, Department of Surgery, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland. 92271 Département de chirurgie (CHIRU) 2184991 10.1080/2162402X.2023.2184991 36891258 2162-4011 PMC9988345 https://www.tandfonline.com/doi/full/10.1080/2162402X.2023.2184991 Nonalcoholic steatohepatitis (NASH) can lead to hepatocellular carcinoma (HCC). Although immunotherapy is used as first-line treatment for advanced HCC, the impact of NASH on anticancer immunity is only partially characterized. We assessed the tumor-specific T cell immune response in the context of NASH. In a mouse model of NASH, we observed an expansion of the CD44+CXCR6+PD-1+CD8+ T cells in the liver. After intra-hepatic injection of RIL-175-LV-OVA-GFP HCC cells, NASH mice had a higher percentage of peripheral OVA-specific CD8+ T cells than control mice, but these cells did not prevent HCC growth. In the tumor, the expression of PD-1 on OVA-specific CD44+CXCR6+CD8+ cells was higher in NASH mice suggesting lowered immune activity. Treating mice with an anti-CD122 antibody, which reduced the number of CXCR6+PD-1+ cells, we restored OVA-specific CD8 activity, and reduced HCC growth compared to untreated NASH mice. Human dataset confirmed that NASH-affected livers, NASH tissues adjacent to HCC and HCC in patients with NASH exhibited gene expression patterns supporting mouse observations. Our findings demonstrate the immune system fails to prevent HCC growth in NASH, primarily linked to a higher representation of CD44+CXCR6+PD-1+CD8+ T cells. Treatment with an anti-CD122 antibody reduces the number of these cells and prevents HCC growth. Hepatocellular carcinoma Immunotherapy Nonalcoholic steatohepatitis Humans Mice Animals Carcinoma, Hepatocellular / genetics Non-alcoholic Fatty Liver Disease / therapy Non-alcoholic Fatty Liver Disease / metabolism Non-alcoholic Fatty Liver Disease / pathology CD8-Positive T-Lymphocytes Liver Neoplasms / genetics Programmed Cell Death 1 Receptor / metabolism Dewey 612 Dewey 616.07 Dewey 617 Swiss National Science Foundation Impact of the gut-liver axis on de novo and recurrent hepatocellular carcinoma in the presence non-alcoholic fatty liver disease 182471 CH Projects Fondation Francis & Marie-France Minkoff Leenaards Foundation 5489 57 Département de chirurgie 222 134 Département de physiologie cellulaire et métabolisme 21C 137 Département de pathologie et immunologie 21F false 562 Transplantation et hépatologie 905 391 Métastases du foie 657 Oncoimmunology 12 1 5b75f2ce-b254-474d-8b30-7e8bf3b627d9 Article (Published version) Public Article-scientifique-from-europePmc.pdf 4248630 application/pdf CC BY-NC-4.0 133d95bec260795f26f7526811bf09e3ec141241204809b5c1a934fd26bee55c 4f52bced-087d-4ce1-87c4-b60a71550491 Appendix Public KONI_A_2184991_SM7374.docx 1741833 application/vnd.openxmlformats-officedocument.wordprocessingml.document 731db0cda0eacc3f561d1b354231b67eaf17f34de8e4ed15442adf1e872e380e openAccess Faculté de médecine / Section de médecine clinique / Département de chirurgie Faculté de médecine / Section de médecine fondamentale / Département de physiologie cellulaire et métabolisme Faculté de médecine / Section de médecine fondamentale / Département de pathologie et immunologie

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Anti-CD122 antibody restores specific CD8⁺ T cell response in nonalcoholic steatohepatitis and prevents hepatocellular carcinoma growth	Oncoimmunology			2023	147	219

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Koenig, Stéphan Hans