小柯机器人

加拿大麦克马斯特大学Ali A. Ashkar研究组发现，代谢的灵活性决定了人类NK细胞在肿瘤微环境中的功能命运。相关论文于2021年4月13日在线发表于国际学术期刊《细胞—代谢》。

通过使用癌症患者的样本和蛋白质组学，研究人员发现肿瘤微环境中的人类NK细胞功能异常是由于脂质过氧化相关的氧化应激抑制葡萄糖代谢所致。Nrf2抗氧化剂途径的激活恢复了NK细胞的代谢和功能，并在体内产生了更大的抗肿瘤活性。令人惊讶的是，扩增的NK细胞以完全的代谢底物灵活性进行了重新编程，不仅保持了持续的代谢适应性，而且反常地增加了其在肿瘤微环境中以及对营养缺乏的杀伤力。这些研究结果表明，代谢灵活性使细胞毒性免疫细胞能够利用肿瘤的代谢不利性发挥其优势，从而解决了癌症免疫治疗的关键障碍。

据悉，NK细胞是抗肿瘤免疫的关键，最近显示出可治疗血液系统恶性肿瘤的功效。然而，它们在不利肿瘤微环境中的功能障碍仍然是实体瘤免疫疗法的关键性障碍。

附：英文原文

Title: Metabolic flexibility determines human NK cell functional fate in the tumor microenvironment

Author: Sophie M. Poznanski, Kanwaldeep Singh, Tyrah M. Ritchie, Jennifer A. Aguiar, Isabella Y. Fan, Ana L. Portillo, Eduardo A. Rojas, Fatemeh Vahedi, Abdullah El-Sayes, Sansi Xing, Martin Butcher, Yu Lu, Andrew C. Doxey, Jonathan D. Schertzer, Hal W. Hirte, Ali A. Ashkar

Issue&Volume: 2021-04-13

Abstract: NK cells are central to anti-tumor immunity and recently showed efficacy for treatinghematologic malignancies. However, their dysfunction in the hostile tumor microenvironmentremains a pivotal barrier for cancer immunotherapies against solid tumors. Using cancerpatient samples and proteomics, we found that human NK cell dysfunction in the tumormicroenvironment is due to suppression of glucose metabolism via lipid peroxidation-associatedoxidative stress. Activation of the Nrf2 antioxidant pathway restored NK cell metabolismand function and resulted in greater anti-tumor activity in vivo. Strikingly, expanded NK cells reprogrammed with complete metabolic substrate flexibilitynot only sustained metabolic fitness but paradoxically augmented their tumor killingin the tumor microenvironment and in response to nutrient deprivation. Our resultsuncover that metabolic flexibility enables a cytotoxic immune cell to exploit themetabolic hostility of tumors for their advantage, addressing a critical hurdle forcancer immunotherapy.

DOI: 10.1016/j.cmet.2021.03.023

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(21)00130-3

Cell Metabolism：《细胞—代谢》，创刊于2005年。隶属于细胞出版社，最新IF：31.373
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