美国约翰霍普金斯大学Jonathan D. Powell及其团队发现，谷氨酰胺阻断能够诱导不同的代谢程序，从而克服肿瘤的免疫逃逸。2019年11月7日，《科学》在线发表了这一研究成果。

使用一种新型的谷氨酰胺拮抗剂，研究人员在代谢上消除了肿瘤的免疫抑制性微环境。研究证明了在荷瘤小鼠中谷氨酰胺的阻滞，抑制了癌细胞的氧化和糖酵解代谢，从而导致缺氧、酸中毒和营养消耗减少。相反，效应T细胞通过显著上调氧化代谢并采用长时间、高度活化的表型来响应谷氨酰胺拮抗作用。细胞代谢和重塑中的这些不同变化形成了有效的抗肿瘤反应的基础。因此，谷氨酰胺拮抗作用暴露了癌细胞和效应T细胞之间代谢可塑性的未知差异，其可被用作肿瘤免疫疗法的“代谢检查点”。

据悉，肿瘤的代谢特征为免疫细胞功能和癌症免疫疗法带来了重大障碍。

附：英文原文

Title: Glutamine blockade induces divergent metabolic programs to overcome tumor immune evasion

Author: Robert D. Leone, Liang Zhao, Judson M. Englert, Im-Meng Sun, Min-Hee Oh, Im-Hong Sun, Matthew L. Arwood, Ian A. Bettencourt, Chirag H. Patel, Jiayu Wen, Ada Tam, Richard L. Blosser, Eva Prchalova, Jesse Alt, Rana Rais, Barbara S. Slusher, Jonathan D. Powell

Issue&Volume: 2019/11/07

Abstract: AbstractThe metabolic characteristics of tumors present significant hurdles to immune cell function and cancer immunotherapy. Using a novel glutamine antagonist, we metabolically dismantled the immunosuppressive microenvironment of tumors. We demonstrate that glutamine blockade in tumor-bearing mice suppresses oxidative and glycolytic metabolism of cancer cells, leading to decreased hypoxia, acidosis, and nutrient depletion. In contrast, effector T cells responded to glutamine antagonism by markedly upregulating oxidative metabolism and adopting a long-lived, highly-activated phenotype. These divergent changes in cellular metabolism and programming form the basis for potent anti-tumor responses. Glutamine antagonism therefore exposes a previously undefined difference in metabolic plasticity between cancer cells and effector T cells that can be exploited as a “metabolic checkpoint” for tumor immunotherapy.

DOI: 10.1126/science.aav2588

Source: https://science.sciencemag.org/content/early/2019/11/06/science.aav2588