肿瘤细胞治疗研究
英文原题：Targeting of Nrf2 improves antitumoral responses by human NK cells, TIL and CAR T cells during oxidative stress.
Targeting of Nrf2 improves antitumoral responses by human NK cells, TIL and CAR T cells during oxidative stress.
这些新发现提示，人细胞毒性淋巴细胞中的 Nrf2 激活可用于增强过继细胞治疗的疗效。
背景：采用细胞毒性淋巴细胞进行过继细胞治疗，是治疗实体瘤和血液系统癌症的有效免疫疗法。然而，肿瘤微环境中活性氧（ROS）水平升高会损害NK和T细胞功能。金化合物auranofin是转录因子Nrf2的强效激活剂；Nrf2可调控多种下游靶基因，帮助细胞增强对ROS的抵抗。本研究提出使用auranofin使人细胞毒性淋巴细胞抵抗氧化应激。方法：对黑色素瘤患者来源TIL、健康供者来源NK细胞及靶向CD19的CAR-T细胞进行低剂量auranofin预处理。在氧化应激条件下，通过肿瘤杀伤实验、脱颗粒/CD107a、细胞因子产生及流式检测细胞内ROS水平，评估其抵抗氧化应激的能力。为确认作用依赖Nrf2，研究通过qPCR检测Nrf2调控的靶基因转录水平。结果：低剂量auranofin在体外预处理人TIL和NK细胞，显著降低细胞内ROS积累，并在高浓度H2O2或单核细胞来源ROS存在时保留抗肿瘤活性。此外，auranofin预处理CD19 CAR-T细胞或TIL，可增强其清除CD19+肿瘤细胞或自体肿瘤球体的能力，ROS暴露时效果尤为明显。Nrf2靶基因分析显示，这种抗ROS能力增强依赖Nrf2。结论：这些新发现提示，激活人细胞毒性淋巴细胞中的Nrf2可能用于增强过继细胞治疗疗效。
BACKGROUND: Adoptive cell therapy using cytotoxic lymphocytes is an efficient immunotherapy against solid and hematological cancers. However, elevated levels of reactive oxygen species (ROS) in the hostile tumor microenvironment can impair NK cell and T cell function. Auranofin, a gold (I)-containing phosphine compound, is a strong activator of the transcription factor Nrf2. Nrf2 controls a wide range of downstream targets important for the cells to obtain increased resistance to ROS. In this study, we present a strategy using auranofin to render human cytotoxic lymphocytes resistant toward oxidative stress. METHODS: Melanoma patient-derived tumor infiltrating lymphocytes (TIL) and healthy donor-derived NK cells and CD19-directed CAR T cells were pretreated with a low dose of auranofin. Their resistance toward oxidative stress was assessed by measuring antitumoral responses (killing-assay, degranulation/CD107a, cytokine production) and intracellular ROS levels (flow cytometry) in conditions of oxidative stress. To confirm that the effects were Nrf2 dependent, the transcription level of Nrf2-driven target genes was analyzed by qPCR. RESULTS: Pretreatment of human TIL and NK cells ex vivo with a low-dose auranofin significantly lowered their accumulation of intracellular ROS and preserved their antitumoral activity despite high H 2 O 2 levels or monocyte-derived ROS. Furthermore, auranofin pretreatment of CD19 CAR-T cells or TIL increased their elimination of CD19 +tumor cells or autologous tumor spheroids, respectively, especially during ROS exposure. Analysis of Nrf2-driven target genes revealed that the increased resistance against ROS was Nrf2 dependent. CONCLUSION: These novel findings suggest that Nrf2 activation in human cytotoxic lymphocytes could be used to enhance the efficacy of adoptive cell therapy.
MEMBER ACCOUNT
登录成功会直接打开下一页。
