Enhancing HBV-specific T cell responses through a combination of epigenetic modulation and immune checkpoint inhibition

Abstract

AbstractObjectiveChronic hepatitis B virus (HBV) infection results in the exhaustion of HBV-specific T cells and the development of epigenetic imprints that impair immune responses and limit the effectiveness of immune checkpoint inhibitor (ICI) monotherapy, such as αPD-L1. This study aimed to determine whether the DNA methyltransferase inhibitor decitabine (DAC) can reverse these epigenetic imprints and enhance the efficacy of ICI in restoring HBV-specific T cell responses.MethodsWe investigated HBV-specific CD4+and CD8+T cell responses by 10-dayin vitrostimulation of peripheral blood mononuclear cells (PBMCs) from patients with chronic HBV infection. PBMCs were stimulated with HBV core-specific overlapping peptide pools and HLA-A*02-restricted peptides, including core18and pol455. The immunomodulatory effect of the combination of DAC/αPD-L1 was assessed via flow cytometry. Responder stratification was investigated by comparison of clinical characteristics,ex vivoDNA methylation analysis of PBMCs, and determination of IFNγ plasma levels.ResultsTreatment with DAC and αPD-L1 enhanced HBV-specific CD4+T cell responses in a significant proportion of 53 patients, albeit with variability. The effect was independent of the HBcrAg level.Ex vivoDNA methylation revealed hypermethylation of key genes likeIFNGamong DAC-responders versus non-responders, supported by alteredex vivoIFNγ plasma levels. Further analysis of HBV-specific CD8+T cell responses in 22 HLA-A*02-positive patients indicated distinct response patterns between HBV-core18- and HBV-pol455-specific T cells, with pol455-specific CD8+T cells showing increased susceptibility to DAC/αPD-L1, surpassing αPD-L1 monotherapy response.ConclusionsThe combination of DAC and αPD-L1 shows promising effects in improving HBV-specific T cell responsesin vitro. Our study highlights the potential of remodeling exhaustion-associated epigenetic signatures to enhance HBV-specific T cell restoration, suggesting a novel immunotherapeutic avenue for chronic HBV infections.Graphic AbstractHighlightsRemodeling epigenetic signatures with a DNA methyltransferase inhibitor enhances the effectiveness of immune checkpoint inhibition in restoring HBV-specific T cell responses.Responsiveness is associated with specific IFNγ DNA methylation patterns and plasma levels.Epigenetic remodeling had distinct effects on two CD8 T cell epitopes, with more pronounced effects on HBV-pol455-specific CD8+T cell responses.