The impact of an anti- PD-1 therapy on hepatitis B specific CD4+ and CD8+ T cells.

• Applicant: Dr. Lea Marie Bartsch
• Subject Area: Gastroenterology
• Term: from 2020 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 444927137

• Final Report Year: 2023

Final Report Abstract

Although a hepatitis B vaccination is available since decades, a chronic hepatitis B virus (HBV) infection is still a worldwide burden. Currently, the global prevalence is around 240 million chronically infected people. The available antiviral hepatitis B therapies are extremely effective in suppressing viral replication. However, they only lead to sterilizing cure in a minority of patients, so that a lifelong therapy is required for most patients. In chronic infection, the persistent antigen presentation leads to the development of exhausted T cells which might be causative or contribute to chronic viral persistence. A characteristic of virusspecific exhausted T cells is that they express a variety of inhibitory T cell receptors such as the programmed cell death protein 1 (PD-1). Recent studies demonstrate that the T cell exhaustion can be reversed by modern immunotherapy- for example by anti-PD-1 monoclonal antibody therapy. Thus, the anti-PD-1 therapy could also be a key component of the therapeutic arsenal for the treatment of chronic hepatitis B infection. This research project was planned to be part of a clinical study, investigating the influence of anti- PD-1 therapy in chronic hepatitis B infection. It was planned that patients with chronic hepatitis B infection receive an anti-PD1 therapy. Due to the SARS-CoV-2 pandemic the clinical trial did not start or recruit any patient. As an alternative approach, T cell exhaustion was analyzed in a multicentric international study in paired liver and blood samples of patients with acute, chronic and cured HBV infection. Single cell RNA Seq analysis were performed of virus-specific T cells in order to comprehensively characterize their exhaustion profile and to detect new potential therapeutic targets. In parallel singlecell RNASeq analysis were performed by Seqwell on whole (antigen-unspecific) PBMCs. Collectively, this research project will allow a general but profound insight into T cell exhaustion and define a possible new therapeutic strategy for chronic hepatitis B infection.

Publications

• HIF-1α- and hypoxia-dependent immune responses in human CD4+CD25high T cells and T helper 17 cells. Journal of Leukocyte Biology, 96(2), 305-312.
  Bollinger, Thomas; Gies, Sydney; Naujoks, Julius; Feldhoff, Lea; Bollinger, Annalena; Solbach, Werner & Rupp, Jan
  
• Transcription regulates HIF‐1α expression in CD4+ T cells. Immunology & Cell Biology, 94(1), 109-113.
  Bollinger, Thomas; Bollinger, Annalena; Gies, Sydney; Feldhoff, Lea; Solbach, Werner & Rupp, Jan
  
• Interferon Regulatory Factor 4 controls TH1 cell effector function and metabolism. Scientific Reports, 6(1).
  Mahnke, Justus; Schumacher, Valéa; Ahrens, Stefanie; Käding, Nadja; Feldhoff, Lea Marie; Huber, Magdalena; Rupp, Jan; Raczkowski, Friederike & Mittrücker, Hans-Willi
  
• IL-1β induced HIF-1α inhibits the differentiation of human FOXP3+ T cells. Scientific Reports, 7(1).
  Feldhoff, Lea M.; Rueda, Cesar M.; Moreno-Fernandez, Maria E.; Sauer, Johanna; Jackson, Courtney M.; Chougnet, Claire A. & Rupp, Jan
  
• Intrahepatic TH17/TReg Cells in Homeostasis and Disease—It’s All About the Balance. Frontiers in Pharmacology, 11.
  Drescher, Hannah K.; Bartsch, Lea M.; Weiskirchen, Sabine & Weiskirchen, Ralf
  
• Tissue-Resident Memory T Cells in the Liver—Unique Characteristics of Local Specialists. Cells, 9(11), 2457.
  Bartsch, Lea M.; Damasio, Marcos P. S.; Subudhi, Sonu & Drescher, Hannah K.
  
• Differentiation of exhausted CD8+ T cells after termination of chronic antigen stimulation stops short of achieving functional T cell memory. Nature Immunology, 22(8), 1030-1041.
  Tonnerre, Pierre; Wolski, David; Subudhi, Sonu; Aljabban, Jihad; Hoogeveen, Ruben C.; Damasio, Marcos; Drescher, Hannah K.; Bartsch, Lea M.; Tully, Damien C.; Sen, Debattama R.; Bean, David J.; Brown, Joelle; Torres-Cornejo, Almudena; Robidoux, Maxwell; Kvistad, Daniel; Alatrakchi, Nadia; Cui, Ang; Lieb, David; Cheney, James A. ... & Lauer, Georg M.
  
• Distinct Hepatic Gene‐Expression Patterns of NAFLD in Patients With Obesity. Hepatology Communications, 6(1), 77-89.
  Subudhi, Sonu; Drescher, Hannah K.; Dichtel, Laura E.; Bartsch, Lea M.; Chung, Raymond T.; Hutter, Matthew M.; Gee, Denise W.; Meireles, Ozanan R.; Witkowski, Elan R.; Gelrud, Louis; Masia, Ricard; Osganian, Stephanie A.; Gustafson, Jenna L.; Rwema, Steve; Bredella, Miriam A.; Bhatia, Sangeeta N.; Warren, Andrew; Miller, Karen K.; Lauer, Georg M. & Corey, Kathleen E.
  
• Expression of IGF-1 receptor and GH receptor in hepatic tissue of patients with nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Growth Hormone & IGF Research, 65, 101482.
  Osganian, Stephanie A.; Subudhi, Sonu; Masia, Ricard; Drescher, Hannah K.; Bartsch, Lea M.; Chicote, Mark L.; Chung, Raymond T.; Gee, Denise W.; Witkowski, Elan R.; Bredella, Miriam A.; Lauer, Georg M.; Corey, Kathleen E. & Dichtel, Laura E.
  
• Hepatitis B virus-specific CD4 T cell responses differentiate functional cure from chronic surface antigen+ infection. Journal of Hepatology, 77(5), 1276-1286.
  Hoogeveen, Ruben C.; Dijkstra, Suzan; Bartsch, Lea M.; Drescher, Hannah K.; Aneja, Jasneet; Robidoux, Maxwell P.; Cheney, James A.; Timm, Joerg; Gehring, Adam; de Sousa, Paulo Sergio Fonseca; Ximenez, Lya; Peliganga, Luis Baiao; Pitts, Anita; Evans, Fiona B.; Boonstra, André; Kim, Arthur Y.; Lewis-Ximenez, Lia L. & Lauer, Georg M.