2. Academic Validation
  3. Therapeutic potential of co-signaling receptor modulation in hepatitis B

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

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: iannacone.matteo@hsr.it.
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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