Metabolic flexibility determines human NK cell functional fate in the tumor microenvironment
Metabolic flexibility determines human NK cell functional fate in the tumor microenvironment
复制标题
代谢灵活性决定肿瘤微环境中人类 NK 细胞的功能命运
DOI：
10.1016/j.cmet.2021.03.023
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发表时间：
2021-06-01
期刊：
影响因子：
29
通讯作者：
Ashkar, Ali A.
中科院分区：
文献类型：
--
作者：
Poznanski, Sophie M.;Singh, Kanwaldeep;Ashkar, Ali A.
NK细胞是抗肿瘤免疫的中枢细胞，近年来显示出治疗恶性血液病的疗效。然而，它们在恶劣的肿瘤微环境中的功能障碍仍然是针对实体瘤的癌症免疫治疗的关键障碍。利用癌症患者样本和蛋白质组学，我们发现肿瘤微环境中的人NK细胞功能障碍是由于脂质过氧化相关的氧化应激抑制了糖代谢，激活了Nrf2抗氧化途径，恢复了NK细胞的代谢和功能，从而在体内产生了更强的抗肿瘤活性。引人注目的是，具有完全代谢底物灵活性的扩增的NK细胞重新编程，不仅维持了代谢的健康，而且在肿瘤微环境和营养剥夺的反应中，反常地增强了它们对肿瘤的杀伤力。我们的结果发现，代谢灵活性使细胞毒性免疫细胞能够利用肿瘤的代谢敌意获得优势，解决了癌症免疫治疗的关键障碍。
NK cells are central to anti-tumor immunity and recently showed efficacy for treating hematologic malignancies. However, their dysfunction in the hostile tumor microenvironment remains a pivotal barrier for cancer immunotherapies against solid tumors. Using cancer patient samples and proteomics, we found that human NK cell dysfunction in the tumor microenvironment is due to suppression of glucose metabolism via lipid peroxidation-associated oxidative stress, Activation of the Nrf2 antioxidant pathway restored NK cell metabolism and function and resulted in greater anti-tumor activity in vivo. Strikingly, expanded NK cells reprogrammed with complete metabolic substrate flexibility not only sustained metabolic fitness but paradoxically augmented their tumor killing in the tumor microenvironment and in response to nutrient deprivation. Our results uncover that metabolic flexibility enables a cytotoxic immune cell to exploit the metabolic hostility of tumors for their advantage, addressing a critical hurdle for cancer immunotherapy.