TIMM Laboratory, Sahlgrenska Cancer Center, University of Gothenburg, Gothenburg, Sweden.
Department of Psychiatry and Neurochemistry, University of Gothenburg, Gothenburg, Sweden.
Cancer Immunol Res. 2017 Sep;5(9):804-811. doi: 10.1158/2326-6066.CIR-16-0382. Epub 2017 Jul 31.
The NADPH oxidase of myeloid cells, NOX2, generates reactive oxygen species (ROS) to eliminate pathogens and malignant cells. NOX2-derived ROS have also been proposed to dampen functions of natural killer (NK) cells and other antineoplastic lymphocytes in the microenvironment of established tumors. The mechanisms by which NOX2 and ROS influence the process of distant metastasis have only been partially explored. Here, we utilized genetically NOX2-deficient mice and pharmacologic inhibition of NOX2 to elucidate the role of NOX2 for the hematogenous metastasis of melanoma cells. After intravenous inoculation of B16F1 or B16F10 cells, lung metastasis formation was reduced in B6.129S6- (-KO) versus -sufficient wild-type (WT) mice. Systemic treatment with the NOX2-inhibitor histamine dihydrochloride (HDC) reduced melanoma metastasis and enhanced the infiltration of IFNγ-producing NK cells into lungs of WT but not of -KO mice. IFNγ-deficient B6.129S7- /J mice were prone to develop melanoma metastases and did not respond to treatment with HDC. We propose that NOX2-derived ROS facilitate metastasis of melanoma cells by downmodulating NK-cell function and that inhibition of NOX2 may restore IFNγ-dependent, NK cell-mediated clearance of melanoma cells. .
髓样细胞中的 NADPH 氧化酶，NOX2，产生活性氧物质（ROS）以消除病原体和恶性细胞。NOX2 衍生的 ROS 也被提出可以抑制自然杀伤（NK）细胞和其他抗肿瘤淋巴细胞在已建立的肿瘤微环境中的功能。NOX2 和 ROS 影响远处转移过程的机制仅部分得到了探索。在这里，我们利用基因敲除 NOX2 的小鼠和 NOX2 的药理学抑制作用，阐明了 NOX2 对黑色素瘤细胞血源性转移的作用。在静脉接种 B16F1 或 B16F10 细胞后，B6.129S6-（-KO）与野生型（WT）小鼠相比，肺转移形成减少。系统给予 NOX2 抑制剂盐酸组氨酸（HDC）可减少黑色素瘤转移，并增强 IFNγ 产生的 NK 细胞浸润到 WT 小鼠的肺部，但不能浸润到 -KO 小鼠的肺部。IFNγ 缺陷型 B6.129S7- / J 小鼠易发生黑色素瘤转移，且对 HDC 治疗无反应。我们提出，NOX2 衍生的 ROS 通过下调 NK 细胞功能促进黑色素瘤细胞转移，而抑制 NOX2 可能恢复 IFNγ 依赖性、NK 细胞介导的黑色素瘤细胞清除。
