Kim Joo-Young, Bae Jae-Ho, Lee Sang-Hwa, Lee Eun-Yup, Chung Byung-Seon, Kim Sun-Hee, Kang Chi-Dug
Department of Biochemistry, Pusan National University School of Medicine, Pusan National University, Busan, Korea.
J Immunother. 2008 Jun;31(5):475-86. doi: 10.1097/CJI.0b013e3181755deb.
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.
自然杀伤（NK）细胞是对肿瘤细胞免疫应答中的重要效应细胞，NK细胞的激活通过激活受体与其同源配体之间的特异性相互作用介导。最近，已证明各种应激诱导肿瘤细胞上的NKG2D配体使其对NK细胞介导的杀伤更敏感。因此，在本研究中，研究了三氧化二砷（ATO）是否能上调肿瘤细胞上的NKG2D配体并增加癌细胞对NK细胞的敏感性。ATO增加了各种癌细胞系中NKG2D配体（主要是ULBP1）的转录，如K562慢性粒细胞白血病细胞、NB4急性早幼粒细胞白血病细胞和MCF7乳腺癌细胞，随后增加了NKG2D配体的表面表达。这些结果之后是ATO处理后癌细胞对NK细胞介导的细胞毒性的敏感性增加。加入阻断性NKG2D单克隆抗体可消除这种细胞毒性的增加，表明ATO处理的癌细胞对NK细胞细胞毒性敏感性的增加是通过上调NKG2D配体介导的。此外，用KNK437消除热休克蛋白的诱导会使ATO处理的MCF-7细胞对NK细胞介导的杀伤敏感。本研究表明，ATO的免疫调节特性将是提高基于NK细胞的癌症免疫治疗有效性的有吸引力的策略。
