Manipulating the 4-1BB Pathway to Cure HBV

Chronic Hepatitis B Virus (HBV) infection is a major global health issue leading to liver cirrhosis and hepatocellular carcinoma. Currently available treatments have limited efficacy in completely eradicating the virus.^[1] The persistence of HBV is largely due to the virus’s ability to induce a dysfunctional state in CD8+ T cells. One of the critical questions is why HBV-specific CD8+ T cells become dysfunctional and how this dysfunction can be reversed.^[2,3]

It is hypothesized that co-signaling receptors, which play a pivotal role in T cell activation and regulation, are key to this process. Thus, understanding the expression and modulation of these receptors may help to identify therapeutic targets that can restore the functionality of these T cells. This approach is based on the observation that traditional immune checkpoint inhibitors, which have shown success in other chronic infections and cancers, have minimal impact on reversing HBV-induced T cell dysfunction,^[4] and therefore, alternative co-signaling receptors may be more effective in this context.

In a recent study by Andreata et al,^[5] the researchers conducted an in-depth analysis of co-signaling receptor modulation in HBV-specific CD8+ T cells to address their dysfunction in chronic HBV infection. This study utilized a combination of in vivo mouse models, bulk and single-cell RNA sequencing, and various immunological assays to identify key co-signaling receptors that are upregulated during hepatocellular priming and examine their potential as therapeutic targets. While blocking co-inhibitory receptors, such as PD-1, CTLA-4, and LAG-3, showed minimal efficacy, the activation of the co-stimulatory receptors 4-1BB and OX40 significantly restored T-cell function. Specifically, intrahepatically primed dysfunctional HBV-specific T cells consisted of a dysfunctional progenitor or stem-like (TSL) population and two distinct dysfunctional tissue-resident memory (TRM) cell populations. All three subsets maintained 4-1BB expression, while OX40 expression was limited to TSL. 4-1BB agonism was highlighted as the most promising strategy, capable of converting all three subpopulations into effective antiviral effectors. Finally, in patients with HBeAg+ CHB infection, 4-1BB activation can rejuvenate dysfunctional CD8+ T cells. This study provides a detailed exploration of the molecular mechanisms underlying T cell dysfunction and demonstrates the therapeutic potential of activating the co-stimulatory receptor 4-1BB on HBV-specific CD8+ T cells to overcome the dysfunction induced by chronic HBV infection, thereby restoring their antiviral activity.

The primary findings of the abovementioned study are based on experiments with monoclonal T cell lines in mice, which differ from the polyclonal T cell responses observed in patients at various stages of infection. HBV-specific T cells showed high heterogeneity in the quantity and functional characteristics, influenced by the targeted epitopes and the patient’s disease stage. For example, HBV-specific T cells were rarely detected directly ex vivo in samples from chronic patients with high levels of HBV viremia. Moreover, Env-specific CD8+ T-cells were found to be more dysfunctional than polymerase- or core-specific CD8+ T-cells.^[6,7] The responsivity of HBV-specific T cells to immune checkpoint interventions also varies.^[8] Moreover, T cell functionality is regulated not only by antigen and co-stimulation but also by cytokines (such as IL-2) and metabolic mechanisms.^[9,10] Therefore, further investigation is needed to understand the synergistic interactions among co-stimulatory signals, cytokines, and metabolic factors.

In conclusion, this study provides compelling evidence that targeting the co-stimulatory receptor 4-1BB can effectively restore the functionality of HBV-specific CD8+ T cells. This offers a promising new approach to the treatment of chronic HBV infection, which may be facilitated by the development of new-generation 4-1BB agonistic drugs with improved safety and tolerability.^[11] In addition, 4-1BB presents a potential target for optimizing T-cell-based therapeutic strategies.

Conflicts of Interest

None.

Editor note: Fu-Sheng Wang is the editor of Infectious Diseases & Immunity. The article was subject to the journal’s standard procedures, with peer review handled independently by this editor and his research group.

Funding Statement

This work was supported by the National Key Research and Development Program of China (2022YFA1303600 and 2023YFC2308100) and the National Natural Science Foundation of China (82130019).