Therapeutic potential of co-signaling receptor modulation in hepatitis B
Francesco Andreata, Chiara Laura, Micol Ravà, Caroline C. Krueger, Xenia Ficht, Keigo Kawashima, Cristian G. Beccaría, Federica Moalli, Bianca Partini, Valeria Fumagalli, Giulia Nosetto, Pietro Di Lucia, Ilaria Montali, José Manuel García-Manteiga, Elisa Bono, Leonardo Giustini, Chiara Perucchini, Valentina Venzin, Serena Ranucci, Donato Inverso, Marco De Giovanni, Marco Genua, Renato Ostuni, Enrico Lugli, Masanori Isogawa, Carlo Ferrari, Carolina Boni, Paola Fisicaro, Luca G. Guidotti, Matteo Iannacone
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 (T SL ) cells and two distinct dysfunctional tissue-resident memory (T RM ) populations. While 4-1BB expression is ubiquitously maintained, OX40 expression is limited to T SL . 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.