HDAC inhibitors and immunotherapy; a double edged sword?

Michiel Kroesen, Paul R. Gielen, Ingrid C. Brok, Inna Armandari, Peter M. Hoogerbrugge and Gosse J. Adema _

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Oncotarget. 2014; 5:6558-6572. https://doi.org/10.18632/oncotarget.2289

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Michiel Kroesen1,2, Paul R. Gielen1,*, Ingrid C. Brok1,*, Inna Armandari1, Peter M. Hoogerbrugge2,3 and Gosse J. Adema1

1 Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, Nijmegen, The Netherlands

2 Department of Pediatric Oncology, Radboud University Medical Centre, Nijmegen, The Netherlands

3 Princes Máxima Center for Pediatric Oncology, The Bilt, The Netherlands

* These authors contributed equally to this work


Gosse J. Adema, email:

Keywords: HDAC inhibitor, cancer, immunotherapy, immunocombination therapy

Received: June 27, 2014 Accepted: July 31, 2014 Published: July 31, 2014


Epigenetic modifications, like histone acetylation, are essential for regulating gene expression within cells. Cancer cells acquire pathological epigenetic modifications resulting in gene expression patterns that facilitate and sustain tumorigenesis. Epigenetic manipulation therefore is emerging as a novel targeted therapy for cancer. Histone Acetylases (HATs) and Histone Deacetylases (HDACs) regulate histone acetylation and hence gene expression. 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. Immunotherapy can lead to clinical benefit in selected cancer patients, especially in patients with limited disease after tumor debulking. HDAC inhibitors can potentially synergize with immunotherapy by elimination of tumor cells. The direct effects of HDAC inhibitors on immune cell function, however, remain largely unexplored. Initial data have suggested HDAC inhibitors to be predominantly immunosuppressive, but more recent reports have challenged this view. In this review we will discuss the effects of HDAC inhibitors on tumor cells and different immune cell subsets, synergistic interactions and possible mechanisms. Finally, we will address future challenges and potential application of HDAC inhibitors in immunocombination therapy of cancer.

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