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

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Enhancing HBV-specific T cell responses through a combination of epigenetic modulation and immune checkpoint inhibition
Hepatology ( IF 12.9 ) Pub Date : 2024-12-19 , DOI: 10.1097/hep.0000000000001202
Melanie Urbanek-Quaing, Yin-Han Chou, Manoj Kumar Gupta, Katja Steppich, Birgit Bremer, Hagen Schmaus, Katja Deterding, Benjamin Maasoumy, Heiner Wedemeyer, Cheng-Jian Xu, Anke R. M. Kraft, Markus Cornberg

Objective: Chronic HBV infection (CHB) exhausts HBV-specific T cells, develops epigenetic imprints that impair immune responses, and limits the effectiveness of immune checkpoint inhibitor (ICI) monotherapy, such as αPD-L1. This study aimed to determine whether the DNA methyltransferase inhibitor decitabine (DAC) could reverse these epigenetic imprints and enhance ICI efficacy in restoring HBV-specific T cell responses. Methods: We investigated HBV-specific T cell responses by 10-day in vitro stimulation of peripheral blood mononuclear cells (PBMCs) from patients with CHB. PBMCs were stimulated with HBV core-specific overlapping peptide pools and HLA-A*02-restricted peptides, core18 and pol455. 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. Results: 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 core18 and pol455 stimulation, with pol455-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 CHB.

更新日期：2024-12-19

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