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

Abstract

ObjectiveChronic 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 PD-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-day in vitro stimulation 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 core18 and pol455. The immunomodulatory effect of the combination of DAC/PD-L1 was assessed via flow cytometry. Responder stratification was investigated by comparison of clinical characteristics, ex vivo DNA methylation analysis of PBMCs, and determination of IFN{gamma} plasma levels. ResultsTreatment with DAC and PD-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 vivo DNA methylation revealed hypermethylation of key genes like IFNG among DAC-responders versus non-responders, supported by altered ex vivo IFN{gamma} 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/PD-L1, surpassing PD-L1 monotherapy response. ConclusionsThe combination of DAC and PD-L1 shows promising effects in improving HBV-specific T cell responses in 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 Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=129 SRC="FIGDIR/small/611632v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@156d0fborg.highwire.dtl.DTLVardef@b22d2corg.highwire.dtl.DTLVardef@1b3c4e2org.highwire.dtl.DTLVardef@1430bbf_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIRemodeling epigenetic signatures with a DNA methyltransferase inhibitor enhances the effectiveness of immune checkpoint inhibition in restoring HBV-specific T cell responses. C_LIO_LIResponsiveness is associated with specific IFN{gamma} DNA methylation patterns and plasma levels. C_LIO_LIEpigenetic remodeling had distinct effects on two CD8 T cell epitopes, with more pronounced effects on HBV-pol455-specific CD8+ T cell responses. C_LI