Histone deacetylase inhibitors sensitize tumour cells for cytotoxic effects of natural killer cells

Schmudde, Mareike; Braun, André; Pende, Daniela; Sonnemann, Jürgen; Klier, Ulrike; Beck, James F.; Moretta, Alessandro; Bröker, Barbara M.

doi:10.1016/j.canlet.2008.06.027

Cited by 65 publications

(62 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In this study, we showed that VPA elevated the expression of MICA and B on the surface of osteosarcoma cells and enhanced their susceptibility to the cytotoxicity of NK cells as reported with other tumor cells (6)(7)(8)(9)(10)(11). On the other hand, levels of soluble MICA and B were not changed or rather decreased in the presence of VPA.…”

Section: Discussionsupporting

confidence: 74%

“…HDAC inhibitors which alter the histone acetylation status have been shown to induce cell cycle arrest and apoptosis in various tumor cells (4,5). In addition, HDAC inhibitors stimulate the expression of cellsurface MICA and B on tumor cells to enhance cytotoxicity of NK cells and host immune surveillance against tumor cells (6)(7)(8)(9)(10)(11).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Sodium valproate, a histone deacetylase inhibitor, augments the expression of cell-surface NKG2D ligands, MICA/B, without increasing their soluble forms to enhance susceptibility of human osteosarcoma cells to NK cell-mediated cytotoxicity

Yamanegi

Yamane²,

Kobayashi³

et al. 2010

Oncol Rep

View full text Add to dashboard Cite

Abstract. MHC class I-related chain molecules A and B (MICA and B) expressed on the cell-surface of tumor cells are ligands for an activating receptor, NKG2D, expressed on natural killer (NK) cells and stimulate the NK cell-mediated cytotoxicity. On the other hand, the soluble form of MICA and B produced by proteolytic cleavage of cell-surface MIC interferes with NK cell-mediated cytotoxicity. We investigated effect of sodium valproate (VPA), a histone deacetylase inhibitor, on the production of cell-surface and soluble MICA and B and NK cell-mediated cytotoxicity in four human osteosarcoma cells. VPA at 0.5 and 1.0 mM induced acetylation of histones bound to MICA and B gene promoters, increased cell-surface but not soluble MICA and B, and augmented the susceptibility of osteosarcoma cells to NK cell-mediated cytotoxicity. The present results indicate that VPA sensitizes human osteosarcoma cells to cytotoxicity of NK cells.

show abstract

Section: Discussionsupporting

confidence: 74%

Section: Introductionmentioning

confidence: 99%

Sodium valproate, a histone deacetylase inhibitor, augments the expression of cell-surface NKG2D ligands, MICA/B, without increasing their soluble forms to enhance susceptibility of human osteosarcoma cells to NK cell-mediated cytotoxicity

Yamanegi

Yamane²,

Kobayashi³

et al. 2010

Oncol Rep

View full text Add to dashboard Cite

show abstract

“…A number of studies have demonstrated that HDAC inhibitors stimulate the expression of cell surface MICA and MICB in a variety of tumors (12)(13)(14)(15). Valproic acid (VPA), a HDAC inhibitor, increases the expression of MICA and MICB on the surface of human osteosarcoma cells (16).…”

Section: Introductionmentioning

confidence: 99%

Downregulation of matrix metalloproteinase-9 mRNA by valproic acid plays a role in inhibiting the shedding of MHC class I-related molecules A and B on the surface of human osteosarcoma cells

et al. 2012

View full text Add to dashboard Cite

Abstract. Valproic acid, a histone deacetylase inhibitor, increases the expression of cell surface MHC class I-related chain molecules (MICs) A and B (MICA and B) in osteosarcoma cells and decreases their secretion of soluble MICA and MICB, which are produced by the proteolytic cleavage of cell surface MICs. Osteosarcoma cells have been reported to produce high levels of matrix metalloproteinase (MMP)-2 and -9. In this study, we investigated the involvement of MMP-2 and -9 in the inhibitory action of valproic acid (VPA) on the proteolytic cleavage of cell surface MICs using the U-2 OS and SaOS-2 osteosarcoma cell lines. VPA caused a marked decrease in the expression of MMP-9 mRNA in the U-2 OS and SaOS-2 cells and in the expression of MMP-2 mRNA in the U-2 OS cells, but only a slight decrease in the expression of MMP-2 mRNA in the SaOS-2 cells. The transfection of small interfering RNA (siRNA) for MMP-9 decreased the secretion of soluble MICA and MICB by both U-2 OS and SaOS-2 cells, but that of siRNA for MMP-2 did not. The present study therefore demonstrates that the downregulation of MMP-9 mRNA by VPA plays a role in the inhibitory action of VPA on the secretion of soluble MICA and MICB in osteosarcoma cells.

show abstract

“…54 Another study reported that treatment of DAOY (medulloblastoma) and PC-3 cells with multiple HDAC inhibitors resulted in elevated expression of MIC-A/B, ULBP1-3, CD112, and CD155, and enhanced lysis of these cells by IL-2‒activated PBMCs. 53 A third study demonstrated that exposure of Ewing sarcoma cells to HDAC inhibitors elevated the expression of MIC-A/B, ULBP1-3, CD112, and CD155 and enhanced their lysis by IL-15 activated NK cells. 52 Importantly, in our studies, both inhibitors were used with clinically relevant exposures in an attempt to closely approximate effects that would be seen in patients.…”

Section: Discussionmentioning

confidence: 99%

Epigenetic priming of both tumor and NK cells augments antibody-dependent cellular cytotoxicity elicited by the anti-PD-L1 antibody avelumab against multiple carcinoma cell types

et al. 2018

View full text Add to dashboard Cite

Checkpoint inhibitors targeting the PD-1/PD-L1 axis are promising immunotherapies shown to elicit objective responses against multiple tumor types, yet these agents fail to benefit most patients with carcinomas. This highlights the need to develop effective therapeutic strategies to increase responses to PD-1/PD-L1 blockade. Histone deacetylase (HDAC) inhibitors in combination with immunotherapies have provided preliminary evidence of anti-tumor effects. We investigated here whether exposure of either natural killer (NK) cells and/or tumor cells to two different classes of HDAC inhibitors would augment (a) NK cell‒mediated direct tumor cell killing and/or (b) antibody-dependent cellular cytotoxicity (ADCC) using avelumab, a fully human IgG1 monoclonal antibody targeting PD-L1. Treatment of a diverse array of human carcinoma cells with a clinically relevant dose of either the pan-HDAC inhibitor vorinostat or the class I HDAC inhibitor entinostat significantly enhanced the expression of multiple NK ligands and death receptors resulting in enhanced NK cell‒mediated lysis. Moreover, HDAC inhibition enhanced tumor cell PD-L1 expression both in vitro and in carcinoma xenografts. These data demonstrate that treatment of a diverse array of carcinoma cells with two different classes of HDAC inhibitors results in enhanced NK cell tumor cell lysis and avelumab-mediated ADCC. Furthermore, entinostat treatment of NK cells from healthy donors and PBMCs from cancer patients induced an activated NK cell phenotype, and heightened direct and ADCC-mediated healthy donor NK lysis of multiple carcinoma types. This study thus extends the mechanism and provides a rationale for combining HDAC inhibitors with PD-1/PD-L1 checkpoint blockade to increase patient responses to anti-PD-1/PD-L1 therapies.

show abstract

Histone deacetylase inhibitors sensitize tumour cells for cytotoxic effects of natural killer cells

Cited by 65 publications

References 47 publications

Sodium valproate, a histone deacetylase inhibitor, augments the expression of cell-surface NKG2D ligands, MICA/B, without increasing their soluble forms to enhance susceptibility of human osteosarcoma cells to NK cell-mediated cytotoxicity

Sodium valproate, a histone deacetylase inhibitor, augments the expression of cell-surface NKG2D ligands, MICA/B, without increasing their soluble forms to enhance susceptibility of human osteosarcoma cells to NK cell-mediated cytotoxicity

Downregulation of matrix metalloproteinase-9 mRNA by valproic acid plays a role in inhibiting the shedding of MHC class I-related molecules A and B on the surface of human osteosarcoma cells

Epigenetic priming of both tumor and NK cells augments antibody-dependent cellular cytotoxicity elicited by the anti-PD-L1 antibody avelumab against multiple carcinoma cell types

Contact Info

Product

Resources

About