Enhancing HBV-Specific T Cell Responses through Epigenetic Modulation and Immune Checkpoint Inhibition in Chronic HBV Infection

Chronic HBV infection (CHB) leads to exhaustion of HBV-specific T cell responses and epigenetic imprints. These epigenetic signatures prevent a robust immune response. Given the limited success of immune checkpoint inhibitor therapies (e.g., αPD-L1), we aim to target this epigenetic imprinting with the epigenetic modifying DNA methyltransferase inhibitor decitabine (DAC) in combination with αPD-L1 to assess whether the combination can improve HBV-specific T cell immune responses.

We performed 10-day in-vitro culture with peripheral blood mononuclear cells (PBMC) from 56 CHB patients and stimulated the cells with either HBV core overlapping peptide pool (n=54) or HLA-A2-restricted peptides (n=22), core18 and pol455. PBMCs were treated with DAC with or without the addition of αPD-L1 on day 3 post-stimulation. The IFNγ response of CD4+and CD8+T cells was analyzed by flow cytometry.

DAC and αPD-L1 combination could indeed improve IFNγ responses. The HBV core-specific CD4+IFNγ response showed an 2- to 100-fold increase by the combination of DAC/αPD-L1 compared with αPD-L1 in some patients, but the responses were highly heterogeneous. Interestingly, DNA methylation analysis of PBMC of the top responders and top nonresponders revealed different epigenetic patterns. For CD8+T cell responses, pol455-specific CD8+T cells showed significantly enhanced response to DAC/αPD-L1 compared with αPD-L1 alone (effect size d=0.47), whereas core18 responses were highly heterogeneous.

In conclusion, our data support the importance of epigenetics in T cell exhaustion and that modification of epigenetics in combination with immune checkpoint inhibitors has the potential to enhance HBV-specific T cell restoration.

Publication History

Article published online:
23 January 2024