Abstract
Decitabine has been found to have anti-metabolic and anti-tumor activities in various tumor cells. Recently, the use of decitabine in combination with other conventional therapies reportedly resulted in improved anti-tumor activity against various tumors. Ionizing radiation (IR) is widely used as a cancer treatment. Decitabine and IR improve immunogenicity and susceptibility of tumor cells to immune cells by up-regulating the expression of various molecules such as major histocompatibility complex (MHC) class I; natural-killer group 2, member D (NKG2D) ligands; and co-stimulatory molecules. However, the effects of combining decitabine and IR therapies are largely unknown. Our results indicate that decitabine or IR treatment upregulates MHC class I, along with various co-stimulatory molecules in target tumor cells. Furthermore, decitabine and IR combination treatment further upregulates MHC class I, along with the co-stimulatory molecules, when compared to the effect of each treatment alone. Importantly, decitabine treatment further enhanced T cell-mediated cytotoxicity and release of IFN- γ against target tumor cells which is induced by IR. Interestingly, decitabine did not affect NKG2D ligand expression or NK cell-mediated cytotoxicity in target tumor cells. These observations suggest that decitabine may be used as a useful immunomodulator to sensitize tumor cells in combination with other tumor therapies.
Highlights
Ionizing radiation (IR) is widely used as a treatment in cancer patients; it causes double-strand DNA breaks, and induces cancer cell death
These results suggest that treatment with decitabine and/or IR significantly increased the expression of major histocompatibility complex (MHC) class I and co-stimulatory molecules such as CD40 and CD80
Decitabine (Dacogen ) has been used for the treatment of hematological malignancies such as, myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), and it has been recently considered in the treatment of solid tumors
Summary
Ionizing radiation (IR) is widely used as a treatment in cancer patients; it causes double-strand DNA breaks, and induces cancer cell death. IR upregulates immune stimulatory receptors such as Fas/ CD95 and MHC class I, and co-stimulatory molecules. It induces the proinflammatory cytokines interleukin (IL)-1βand tumor necrosis factor (TNF)-α22–25. Co-stimulatory molecules expressed on target cell membranes further increase the T cell response. Previous studies reported that decitabine and IR upregulate the expression of MHC and co-stimulatory molecules on tumor cells, resulting in an efficient anti-tumor T cell response[28,29,30,31]. While previous studies have focused on the effects of decitabine or IR treatment alone, their combined effects on the activity of immune cells have not been reported. We investigated whether decitabine and IR combination treatment enhances tumor cell susceptibility to immune cells, with a focus on T cells
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