The impact of histone deacetylase inhibitors on immune cells and implications for cancer therapy

Many cancers possess the ability to suppress the immune response to malignant cells, thus facilitating tumour growth and invasion, and this has fuelled research to reverse these mechanisms and re-activate the immune system with consequent important therapeutic benefit. One such approach is to use histone deacetylase inhibitors (HDACi), a novel class of targeted therapies, which manipulate the immune response to cancer through epigenetic modification. Four HDACi have recently been approved for clinical use in malignancies including multiple myeloma and T-cell lymphoma. Most research in this context has focussed on HDACi and tumour cells, however, little is known about their impact on the cells of the immune system. Additionally, HDACi have been shown to impact the mechanisms by which other anti-cancer therapies exert their effects by, for example, increasing accessibility to exposed DNA through chromatin relaxation, impairing DNA damage repair pathways and increasing immune checkpoint receptor expression. This review details the effects of HDACi on immune cells, highlights the variability in these effects depending on experimental design, and provides an overview of clinical trials investigating the combination of HDACi with chemotherapy, radiotherapy, immunotherapy and multimodal regimens.