Therapeutic potential of co-signaling receptor modulation in hepatitis B

  • Cell. 2024 Jul 25;187(15):4078-4094.e21. doi: 10.1016/j.cell.2024.05.038.
Francesco Andreata  1 ,  Chiara Laura  2 ,  Micol Ravà  1 ,  Caroline C Krueger  1 ,  Xenia Ficht  1 ,  Keigo Kawashima  3 ,  Cristian G Beccaria  1 ,  Federica Moalli  3 ,  Bianca Partini  1 ,  Valeria Fumagalli  1 ,  Giulia Nosetto  1 ,  Pietro Di Lucia  1 ,  Ilaria Montali  4 ,  José M Garcia-Manteiga  5 ,  Elisa B Bono  3 ,  Leonardo Giustini  3 ,  Chiara Perucchini  3 ,  Valentina Venzin  3 ,  Serena Ranucci  3 ,  Donato Inverso  1 ,  Marco De Giovanni  3 ,  Marco Genua  6 ,  Renato Ostuni  7 ,  Enrico Lugli  8 ,  Masanori Isogawa  9 ,  Carlo Ferrari  10 ,  Carolina Boni  10 ,  Paola Fisicaro  4 ,  Luca G Guidotti  1 ,  Matteo Iannacone  11
Affiliations
  • 1. Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy.
  • 2. Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy; Center for Omics Sciences, IRCCS San Raffaele Scientific Institute, Milan, Italy.
  • 3. Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy.
  • 4. Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy.
  • 5. Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy; Center for Omics Sciences, IRCCS San Raffaele Scientific Institute, Milan, Italy.
  • 6. San Raffaele-Telethon Institute for Gene Therapy (SR-Tiget), Milan, Italy.
  • 7. Vita-Salute San Raffaele University, Milan, Italy; San Raffaele-Telethon Institute for Gene Therapy (SR-Tiget), Milan, Italy.
  • 8. IRCSS Humanitas Research Hospital, Rozzano, Italy.
  • 9. Research Center for Drug and Vaccine Development, National Institute of Infectious Diseases, Tokyo, Japan.
  • 10. Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy; Department of Medicine and Surgery, University of Parma, Parma, Italy.
  • 11. Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy. Electronic address: [email protected].
PMID: 38897196 DOI: 10.1016/j.cell.2024.05.038
Abstract

Reversing CD8+ T cell dysfunction is crucial in treating chronic hepatitis B virus (HBV) Infection, yet specific molecular targets remain unclear. Our study analyzed co-signaling receptors during hepatocellular priming and traced the trajectory and fate of dysfunctional HBV-specific CD8+ T cells. Early on, these cells upregulate PD-1, CTLA-4, LAG-3, OX40, 4-1BB, and ICOS. While blocking co-inhibitory receptors had minimal effect, activating 4-1BB and OX40 converted them into Antiviral effectors. Prolonged stimulation led to a self-renewing, long-lived, heterogeneous population with a unique transcriptional profile. This includes dysfunctional progenitor/stem-like (TSL) cells and two distinct dysfunctional tissue-resident memory (TRM) populations. While 4-1BB expression is ubiquitously maintained, OX40 expression is limited to TSL. In chronic settings, only 4-1BB stimulation conferred Antiviral activity. In HBeAg+ chronic patients, 4-1BB activation showed the highest potential to rejuvenate dysfunctional CD8+ T cells. Targeting all dysfunctional T cells, rather than only stem-like precursors, holds promise for treating chronic HBV Infection.

Keywords
4-1BB; CD8(+) T cells; OX40; T cell dysfunction; chronic viral infection; hepatitis B virus; immunotherapy; liver.
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