Induction of NKG2D ligands and subsequent enhancement of NK cell-mediated lysis of cancer cells by arsenic trioxide.
Natural killer (NK) cells are important effector cells in immune responses to tumor cells and the activation of NK cells is mediated through specific interactions between activating receptors and their cognate ligands. Recently, it has been demonstrated that induction of NKG2D ligands on tumor cells by various stresses render them more sensitive to NK cell-mediated killing. Therefore, in this study, it was investigated whether arsenic trioxide (ATO) could up-regulate NKG2D ligands on tumor cells and increase the susceptibility of cancer cells against NK cells. ATO increased transcription of NKG2D ligands, predominantly ULBP1, in various cancer cell lines, such as K562 chronic myelogenous leukemic cells, NB4 acute promyelocytic leukemic cells, and MCF7 breast cancer cells, and subsequently the surface expression of NKG2D ligands. These results were followed by increased susceptibility of cancer cells to NK cell-mediated cytotoxicity after treatment with ATO. This increase in cytotoxicity was abolished by addition of a blocking NKG2D monoclonal antibody, indicating that the increased susceptibility of ATO-treated cancer cells to cytotoxicity of NK cells was mediated through up-regulation of NKG2D ligands. In addition, abrogation of heat shock proteins induction with KNK437 would sensitize the ATO-treated MCF-7 cells to NK cell-mediated killing. This study suggests that the immunomodulatory property of ATO would be an attractive strategy to improve the effectiveness of NK cell-based cancer immunotherapy.
Kim
Joo-Young
JY
Department of Biochemistry, Pusan National University School of Medicine, Pusan National University, Busan, Korea.
Bae
Jae-Ho
JH
Lee
Sang-Hwa
SH
Lee
Eun-Yup
EY
Chung
Byung-Seon
BS
Kim
Sun-Hee
SH
Kang
Chi-Dug
CD
D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D006801:Humans; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D008024:Ligands; D055655:NK Cell Lectin-Like Receptor Subfamily K; D009369:Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D010087:Oxides / Q000494:pharmacology*; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D055607:Receptors, Natural Killer Cell; D015854:Up-Regulation / Q000187:drug effects
D001152:Arsenicals; C527085:KLRK1 protein, human; D008024:Ligands; D055655:NK Cell Lectin-Like Receptor Subfamily K; D010087:Oxides; D011971:Receptors, Immunologic; D055607:Receptors, Natural Killer Cell; D000077237:Arsenic Trioxide