Poznanski Sophie M, Singh Kanwaldeep, Ritchie Tyrah M, Aguiar Jennifer A, Fan Isabella Y, Portillo Ana L, Rojas Eduardo A, Vahedi Fatemeh, El-Sayes Abdullah, Xing Sansi, Butcher Martin, Lu Yu, Doxey Andrew C, Schertzer Jonathan D, Hirte Hal W, Ashkar Ali A
Department of Medicine, McMaster Immunology Research Centre, McMaster University, Hamilton, ON L8N 3Z5, Canada.
Department of Oncology, McMaster University, Hamilton, ON L8V 5C2, Canada.
Cell Metab. 2021 Jun 1;33(6):1205-1220.e5. doi: 10.1016/j.cmet.2021.03.023. Epub 2021 Apr 13.
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.
自然杀伤（NK）细胞是抗肿瘤免疫的核心，最近在治疗血液系统恶性肿瘤方面显示出疗效。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疗法的关键障碍。利用癌症患者样本和蛋白质组学，我们发现肿瘤微环境中人类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Nrf2抗氧化途径可恢复NK细胞的代谢和功能，并在体内产生更大的抗肿瘤活性。引人注目的是，经完全代谢底物灵活性重编程的扩增NK细胞不仅维持了代谢适应性，而且反常地增强了它们在肿瘤微环境中以及对营养剥夺的肿瘤杀伤能力。我们的研究结果揭示，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来为自身谋利，解决了癌症免疫治疗的一个关键障碍。
