Anticancer Res. 2013 Apr;33(4):1351-60.

The histone deacetylase inhibitor trichostatin a promotes apoptosis and antitumor immunity in glioblastoma cells.

Höring E, Podlech O, Silkenstedt B, Rota IA, Adamopoulou E, Naumann U.

Hertie Institute for Clinical Brain Research and Center Neurology, Department of Vascular Neurology, Laboratory of Molecular Neuro-Oncology, Tübingen, Germany.

 

Abstract

Histone deacetylase inhibitors (HDACi) have been described as multifunctional anticancer agents. The failure of conventional therapy for glioblastoma (GBM) renders this tumor an attractive target for immunotherapy. Innate immune cells, such as natural killer (NK) cells, play a crucial role in antitumor immune responses. Here, we describe how the HDACi trichostatin A (TSA) promotes apoptosis of tumor cells, as well as augments anti-GBM innate immune responses. In vitro treatment of GBM cells with TSA results in an up-regulation of the natural killer group-2 member-D (NKG2D) ligands major histocompatibility complex class I-related chain (MIC)-A and UL16 binding protein (ULBP)-2 at both mRNA and protein levels, rendering them susceptible to NK cell-mediated lysis. In vivo, TSA delays tumor growth of GBM xenografts. Both the in vitro and in vivo antitumor effect of TSA was significantly reduced by blocking NK cell activity. Our data suggest that HDACi, especially in combination with other clinical immunotherapeutical approaches, may be considered in a combined therapeutic approach for GBM.

PMID: 23564772

 

Supplementary

Natural killer (NK) cells are an essential part of the anti-cancer immune response. Glioblastoma (GBM), being the most malignant brain tumour in man, developed potent strategies to overcome NK cell attacks. This includes downregulation of NKG2D ligands such as major histocompatibility complex (MHC) class I-like molecules (MIC)A, MICB and the UL16 binding proteins (ULBP)1-4 on their surfaces. These ligands, expressed on tumor cells, bind to NKG2D, an activating receptor expressed mainly on NK, but also on CD8+ and gd T cells. Through this receptor NK cells prevent the growth of tumors expressing NKG2DL, and blocking this receptor/ligand interaction results in an impaired killing of cancer cells. Induction of MICA expression in GBM cells pushes the NK cell mediated antitumor response in vitro and also delays GBM growth in mice (1). Many immunomodulating genes, and in this regard also NKG2DL, have been shown to be downregulated by histone deacetylation (HDAC). This emphasizes HDAC inhibition being a potent immunotherapeutic anticancer strategy. Indeed, several studies have demonstrated that inhibition of HDAC in tumor cells induces re-expression of NKG2DL on tumor cells, this way propagating their recognition and removal by immune cells.

In GBM we have shown that the HDAC inhibitor Trichostatin A (TSA) induces expression of immune stimulating proteins such as of the toll-like receptor (TLR) ligand and inductor of T cell mediated anti-cancer immunity high-mobility group B1 (HMGB1) protein as well as of the NKG2D ligands MICA and ULBP2, leading to an enhanced killing of GBM cells by immune cells in vitro. In GBM bearing mice, TSA treatment of tumor cells delayed tumor growth, this effect being strictly dependent on the presence of functional NK cells (2, 3). Our results demonstrate the immune-enhancing activity of HDAC inhibition in the treatment of experimental GBM and its putative therapeutic impact. Conclusion: The state of knowledge related to the effects of HDAC inhibition in cancer immunotherapy provides a rationale to further test HDAC inhibitors as anticancer therapeutic agents in future clinical settings.

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REFERENCE

  1. Friese MA, Platten M, Lutz SZ, Naumann U, Aulwurm S, Bischof F, Bühring HJ, Dichgans J, Rammensee HG, Steinle A, Weller M. 2003. MICA/NKG2D-mediated immunogene therapy of experimental gliomas. Cancer Res. 63:8996-9006
  2. Höring E, Podlech O, Silkenstedt B, Rota IA, Naumann U. 2013 The Histone Deacetylase Inhibitor Trichostatin A Promotes Apoptosis and Antitumor Immunity in Glioblastoma Cells. Anticancer Res  33:1351-1360
  3. Adamopoulou E, Naumann U. 2013. HDAC inhibitors and their potential application in human glioblastoma treatment. Onco Immunol 2:eLocation ID: e25219.
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