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

Abstract

BACKGROUND AND AIMS: Chronic HBV infection exhausts HBV-specific T cells, develops epigenetic imprints that impair immune responses, and limits the effectiveness of immune checkpoint inhibitor monotherapy, such as anti-programmed cell death ligand-1 antibody (αPD-L1). This study aimed to determine whether the DNA methyltransferase inhibitor decitabine (DAC) could reverse these epigenetic imprints and enhance immune checkpoint inhibitor efficacy in restoring HBV-specific T cell responses. APPROACH AND RESULTS: We investigated HBV-specific 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, core 18 and pol 455 . The immunomodulatory effect of the DAC/αPD-L1 combination was assessed by flow cytometry, and our analysis included clinical characteristics, ex vivo DNA methylation of PBMCs, and IFNγ plasma levels.Treatment with DAC/αPD-L1 enhanced HBV-specific CD4 + T cell responses in a significant proportion of 53 patients, albeit with some variability. This effect was independent of the HBcrAg levels. Ex vivo DNA methylation revealed hypermethylation of key genes, such as IFNG among DAC-responders versus non-responders, supported by altered ex vivo IFNγ plasma levels. Further analysis of HBV-specific CD8 + T cell responses in 22 HLA-A*02-positive patients indicated distinct response patterns between core 18 and pol 455 stimulation, with pol 455 -specific CD8 + T cells showing increased susceptibility to DAC/αPD-L1, surpassing the αPD-L1 monotherapy response. CONCLUSIONS: The combination of DAC/αPD-L1 shows promise in improving HBV-specific T cell responses in vitro , highlighting the potential of remodeling exhaustion-associated epigenetic signatures to enhance HBV-specific T cell restoration and suggesting a novel immunotherapeutic avenue for chronic HBV infection.