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
{"title":"Enhancing HBV-specific T cell responses through a combination of epigenetic modulation and immune checkpoint inhibition","authors":"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","doi":"10.1101/2024.09.06.611632","DOIUrl":null,"url":null,"abstract":"<strong>Objective</strong>: Chronic 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.\n<strong>Methods</strong>: We investigated HBV-specific CD4<sup>+</sup> and CD8<sup>+</sup> T cell responses by 10-day <em>in vitro</em> 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 core<sub>18</sub> and pol<sub>455</sub>. The immunomodulatory effect of the combination of DAC/αPD-L1 was assessed via flow cytometry. Responder stratification was investigated by comparison of clinical characteristics, <em>ex vivo</em> DNA methylation analysis of PBMCs, and determination of IFNγ plasma levels. <strong>Results</strong>: Treatment with DAC and αPD-L1 enhanced HBV-specific CD4<sup>+</sup> T cell responses in a significant proportion of 53 patients, albeit with variability. The effect was independent of the HBcrAg level. <em>Ex vivo</em> DNA methylation revealed hypermethylation of key genes like IFNG among DAC-responders versus non-responders, supported by altered <em>ex vivo</em> IFNγ plasma levels. Further analysis of HBV-specific CD8<sup>+</sup> T cell responses in 22 HLA-A*02-positive patients indicated distinct response patterns between HBV-core<sub>18</sub>- and HBV-pol<sub>455</sub>-specific T cells, with pol<sub>455</sub>-specific CD8<sup>+</sup> T cells showing increased susceptibility to DAC/αPD-L1, surpassing αPD-L1 monotherapy response. <strong>Conclusions</strong>: The combination of DAC and αPD-L1 shows promising effects in improving HBV-specific T cell responses <em>in vitro</em>. 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.","PeriodicalId":501182,"journal":{"name":"bioRxiv - Immunology","volume":"177 1","pages":""},"PeriodicalIF":0.0000,"publicationDate":"2024-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"bioRxiv - Immunology","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1101/2024.09.06.611632","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0
Abstract
Objective: Chronic 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.
Methods: We 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/αPD-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 IFNγ plasma levels. Results: Treatment 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 vivo DNA methylation revealed hypermethylation of key genes like 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 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. Conclusions: The combination of DAC and αPD-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.