Finally, we will address future challenges and potential application of HDAC inhibitors in immunocombination therapy of cancer. In this review we will discuss the effects of HDAC inhibitors on tumor cells and different immune cell subsets, synergistic interactions and possible mechanisms. Initial data have suggested HDAC inhibitors to be predominantly immunosuppressive, but more recent reports have challenged this view. The direct effects of HDAC inhibitors on immune cell function, however, remain largely unexplored.

HDAC inhibitors can potentially synergize with immunotherapy by elimination of tumor cells. Immunotherapy can lead to clinical benefit in selected cancer patients, especially in patients with limited disease after tumor debulking. Histone deacetylase (HDAC) inhibitors are well known to affect cancer cell viability and biology and are already in use for the treatment of cancer patients. Histone Acetylases (HATs) and Histone Deacetylases (HDACs) regulate histone acetylation and hence gene expression. Epigenetic manipulation therefore is emerging as a novel targeted therapy for cancer. Cancer cells acquire pathological epigenetic modifications resulting in gene expression patterns that facilitate and sustain tumorigenesis. Received: JAccepted: JPublished: JAbstractĮpigenetic modifications, like histone acetylation, are essential for regulating gene expression within cells. Keywords: HDAC inhibitor, cancer, immunotherapy, immunocombination therapy * These authors contributed equally to this work

Adema 1ġ Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, Nijmegen, The NetherlandsĢ Department of Pediatric Oncology, Radboud University Medical Centre, Nijmegen, The Netherlandsģ Princes Máxima Center for Pediatric Oncology, The Bilt, The Netherlands

A Two-Edged Sword by Thomas K. Martin