Targeting epigenetic imprints to modulate HBV-specific T cell responses

Worldwide, over 296 million people have been diagnosed with chronic HBV (CHB) requiring lifelong therapy to reduce disease progression. However, functional cure of CHB (defined by loss of HBsAg) is rarely achieved and emphasizes the need of new therapeutic approaches. Hallmarks of chronic diseases are an impaired immune system and the presence of exhausted T cells with a distinct epigenetic signature. There are several concepts to improve their function, e.g. checkpoint inhibition via αPDL1. Unfortunately, αPDL1 cannot remodel exhaustion-associated epigenetic patterns.

We aim to identify molecular and epigenetic predictors of treatment responsiveness by investigating epigenetic signatures of immune cells in CHB patients. Additionally, we aim to improve the effect of αPDL1 by targeting epigenetic mechanisms.

Preliminary DNA methylation data suggest an increased biological age (predicted by epigenetic age) in CHB. Additionally, the age acceleration correlates with liver stiffness and an elevated CD8+T cell population demonstrating a link between epigenetic changes in CHB patients, clinically relevant markers and immune cell populations.

To improve checkpoint inhibition, we performed 10-day expansion culture with peripheral blood mononuclear cells (PBMC). PBMCs were stimulated with HBV core overlapping peptide pool and treated with a combination of αPDL1 and DNA methyltransferase inhibitor (DNMTi). We observed cytotoxicity of high dose DNMTi on PBMCs. Additionally, some patients had an improved IFNγ+response of CD4+and CD8+T cells after pretreatment with DNMTi followed by aPDL1 treatment at day 3 post-stimulation.

The results indicate that epigenetic signature of T cells might play an important role in CHB immune response.

Publication History

Article published online:
18 January 2023