Resveratrol sensitized leukemia stem cell-like KG-1a cells to cytokine-induced killer cells-mediated cytolysis through NKG2D ligands and TRAIL receptors

Human promyeloblastic leukemia KG-1a cells exhibit many characteristics similar to leukemia stem cells, which are resistant to chemotherapeutic drugs and hyposensitive to cytotoxic cells. Resveratrol (RES), as a member of plant polyphenols, has gained considerable attention due to its ability to prevent cancer from progressing. In this study, the potential of RES to sensitize KG-1a cells to cytolysis of cytokine-induced killer cells (CIKs) through NKG2D ligands and TNF-related apoptosis-inducing ligand (TRAIL) receptors were investigated. Twenty-five micromolars RES was found to inhibit approximately 50% of KG-1a cell growth and had the least growth-inhibition effect on peripheral blood mononuclear cells (PBMCs) after 24 h. Utilizing cytokines including interleukin-2 (IL-2) and interleukin-15 (IL-15) to activate PBMCs, we obtained substantial CD3(+) CD56(+) natural killer cell-like T lymphocytes that secreted cytokine interferon gamma (IFN gamma) and expressed NKG2D and TRAIL on their surfaces (i.e., cytokine-induced killer cells, CIKs). RES was shown to render KG-1a cells susceptible to CIKs-mediated cytolysis estimated by LDH-release assay. This heightened sensitivity correlated with an increase in cell-surface expression of NKG2D ligands and death receptor 4 (DR4), coupled with a downregulation of cell-surface expression of decoy receptor 1 (DcR1) in KG-1a cells. Blocking NKG2D ligands or TRAIL with monoclonal antibodies could abrogate CIKs-mediated cytolysis. These results demonstrated that increased sensitivity of KG-1a cells, modulated by RES to alloreactive CIKs-mediated cytolysis is a phenomenon attributable to induced expression of NKG2D ligands and activation of TRAIL pathway. Thus, resveratrol combined with alloreactive CIKs merits clinical evaluation as a novel and effective immunotherapy strategy to eliminate residual leukemia stem cells.