Dysfunction of Natural Killer Cells by FBP1-Induced Inhibition of Glycolysis during Lung Cancer Progression
Dysfunction of Natural Killer Cells by FBP1-Induced Inhibition of Glycolysis during Lung Cancer Progression
复制标题
肺癌进展过程中 FBP1 诱导的糖酵解抑制导致自然杀伤细胞功能障碍
DOI：
10.1016/j.cmet.2018.06.021
复制
发表时间：
2018-08-07
期刊：
影响因子：
29
通讯作者：
Wei, Haiming
中科院分区：
文献类型：
--
作者：
Cong, Jingjing;Wang, Xianwei;Wei, Haiming
自然杀伤细胞（NK）是一种效应淋巴细胞，在抵抗多种肿瘤中起着关键作用；NK细胞功能障碍常导致肿瘤进展。肿瘤的发展分为起始、促进和进展三个阶段，但在肿瘤发展的不同阶段，NK细胞与肿瘤细胞之间的相互关系知之甚少。在这里，我们证明NK细胞有效地阻止了kras驱动的肺癌的肿瘤起始，但不能阻止肿瘤的促进或肿瘤的进展。此外，NK细胞抗肿瘤作用的丧失与它们在肿瘤促进和进展过程中的功能失调状态密切相关。在机制上，异常的果糖-1,6-二磷酸酶（FBP1）表达在NK细胞中通过抑制糖酵解和损害生存能力引起功能障碍。因此，我们的研究结果显示了NK细胞在肿瘤发展过程中的动态变化，揭示了NK细胞功能障碍的新机制，为基于NK细胞的肿瘤免疫治疗提供了潜在的方向，包括FBP1靶向。
Natural killer (NK) cells are effector lymphocytes with pivotal roles in the resistance against various tumors; dysfunction of NK cells often results in advanced tumor progression. Tumors develop in three stages comprising initiation, promotion, and progression, but little is known about the interrelationships between NK cells and tumor cells at different stages of tumor development. Here, we demonstrated that NK cells prevented tumor initiation potently but did not prevent tumor promotion or tumor progression in Kras-driven lung cancer. Moreover, loss of the antitumor effect in NK cells was closely associated with their dysfunctional state during tumor promotion and progression. Mechanistically, aberrant fructose-1,6-bisphosphatase (FBP1) expression in NK cells elicited their dysfunction by inhibiting glycolysis and impairing viability. Thus, our results show dynamic alterations of NK cells during tumor development and uncover a novel mechanism involved in NK cell dysfunction, suggesting potential directions for NK cell-based cancer immunotherapy involving FBP1 targeting.