Abstract
Tumors can escape from immunity by repressing leukocyte adhesion molecule expression on tumor endothelial cells and by rendering endothelial cells unresponsive to inflammatory activation. This endothelial cell anergy is induced by angiogenic growth factors and results in reduced leukocyte-vessel wall interactions, thereby attenuating infiltration of leukocytes into the tumor. This report describes a novel mechanism of endothelial cell anergy regulation. We recently reported that DNA methyltransferase (DNMT) and histone deacetylase (HDAC) inhibitors have angiostatic activity. Here, we studied whether epigenetic mechanisms regulate this angiogenesis-mediated escape from immunity. We found that DNMT inhibitors 5-aza-2'-deoxycytidine and zebularine, as well as HDAC inhibitor trichostatin A, reexpressed intercellular adhesion molecule-1 (ICAM-1) on tumor-conditioned endothelial cells in vitro, resulting in restored leukocyte-endothelial cell adhesion. In addition, treatment with DNMT or HDAC inhibitors in vivo also restored ICAM-1 expression on tumor endothelial cells from two different mouse tumor models. Furthermore, leukocyte-vessel wall interactions in mouse tumors were increased by these compounds, as measured by intravital microscopy, resulting in enhanced leukocyte infiltration. We show that ICAM-1 down-regulation in tumor endothelial cells is associated with ICAM-1 promoter histone H3 deacetylation and loss of histone H3 Lys(4) methylation but not with DNA hypermethylation. In conclusion, our data show that ICAM-1 is epigenetically silenced in tumor endothelial cells by promoter histone modifications, which can be overcome by DNMT and HDAC inhibitors, suggesting a new molecular mechanism based on which novel therapeutic approaches for cancer can be pursued.
Highlights
Leukocyte rolling on, adhesion to, and diapedesis through the tumor vessel wall are processes of key importance to immune surveillance, as well as to immunotherapy, a well-established anticancer approach [1]
We found that intercellular adhesion molecule-1 (ICAM-1) expression in tumor endothelial cells and leukocyte-endothelial cells adhesion are restored by DNA methyltransferases (DNMT)- and histone deacetylases (HDAC) inhibitors, resulting in enhanced inflammatory infiltration
To examine whether epigenetic mechanisms are involved in regulation of adhesion molecule expression on tumor endothelial cells, the effects of DNMT and HDAC inhibitors on endothelial cell adhesion molecule expression were studied in vitro
Summary
Adhesion to, and diapedesis through the tumor vessel wall are processes of key importance to immune surveillance, as well as to immunotherapy, a well-established anticancer approach [1]. We and others have shown previously that by producing angiogenic factors, such as vascular endothelial cell growth factors (VEGF) and basic fibroblast growth factors (FGF), tumors down-regulate vascular adhesion molecule expression [3,4,5,6]. This angiogenesis-mediated endothelial cell anergy to inflammatory signals results in diminished leukocytevessel wall interactions and, decreased inflammatory infiltration [7, 8]. Considerable promise lies in the further development of epigenetic therapies that already have shown antitumorigenic effects for several malignancies [16,17,18]
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