The HDAC inhibitor zabadinostat is a systemic regulator of adaptive immunity
Geng Liu1, Wojciech Barczak1, Lian Ni Lee2
1Laboratory of Cancer Biology, Department of Oncology, University of Oxford, Old Road Campus Research Building, Oxford, OX3 7DQ, UK.
Abstract:
Protein acetylation plays a key role in regulating cellular processes and is subject to aberrant control in diverse pathologies. Although histone deacetylase (HDAC) inhibitors are approved drugs for certain cancers, it is not known whether they can be deployed in other therapeutic contexts. We have explored the clinical HDAC inhibitor, zabadinostat/CXD101, and found that it is a stand-alone regulator of the adaptive immune response. Zabadinostat treatment increased expression of MHC class I and II genes in a variety of cells, including dendritic cells (DCs) and healthy tissue. Remarkably, zabadinostat enhanced the activity of DCs, and CD4 and CD8 T lymphocytes. Using an antigenic peptide presented to the immune system by MHC class I, zabadinostat caused an increase in antigen-specific CD8 T lymphocytes. Further, mice immunised with covid19 spike protein and treated with zabadinostat exhibit enhanced covid19 neutralising antibodies and an increased level of T lymphocytes. The enhanced humoral response reflected increased activity of T follicular helper (Tfh) cells and germinal centre (GC) B cells. Our results argue strongly that zabadinostat has potential to augment diverse therapeutic agents that act through the immune system.
Insights
The histone deacetylase inhibitor zabadinostat regulates the adaptive immune response by enhancing T cell activity and antibody production. This immune-modulating drug shows potential for augmenting various immunotherapies.
Area of Science:
- Immunology
- Molecular Biology
- Pharmacology
Background:
- Protein acetylation regulates cellular functions, with aberrant control linked to diseases.
- Histone deacetylase (HDAC) inhibitors are used in cancer therapy, but their broader therapeutic potential is unexplored.
- Zabadinostat (CXD101) is a clinical HDAC inhibitor with potential immunomodulatory effects.
Purpose of the Study:
- To investigate zabadinostat's role as an independent regulator of the adaptive immune response.
- To determine zabadinostat's effects on immune cells and antibody production.
- To assess zabadinostat's potential in combination with other immunotherapies.
Main Methods:
- Treatment of various cell types, including dendritic cells (DCs), with zabadinostat.
- Analysis of MHC class I and II gene expression.
- Assessment of DC, CD4 T cell, and CD8 T cell activity.
- In vivo studies using mice immunized with COVID-19 spike protein and treated with zabadinostat.
Main Results:
- Zabadinostat increased MHC class I and II expression in multiple cell types.
- Enhanced activity of DCs, CD4, and CD8 T lymphocytes was observed.
- Zabadinostat treatment led to an increase in antigen-specific CD8 T lymphocytes.
- Mice treated with zabadinostat showed enhanced COVID-19 neutralizing antibodies and T lymphocyte levels.
- Increased activity of T follicular helper (Tfh) cells and germinal center (GC) B cells correlated with enhanced humoral response.
Conclusions:
- Zabadinostat acts as a standalone regulator of the adaptive immune response.
- The drug enhances both cellular and humoral immunity.
- Zabadinostat demonstrates significant potential for augmenting diverse immunotherapeutic agents.
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