Department of Colorectal and Anal Surgery, Zhongnan Hospital of Wuhan University, Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, 430071, China.
Division of Hematology/Oncology, Children's Hospital of Pittsburgh of UPMC, The Department of Microbiology and Molecular Genetics, The Pittsburgh Liver Research Center and The Hillman Cancer Center of UPMC, The University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, 15224, USA.
Adv Sci (Weinh). 2024 Nov;11(43):e2403629. doi: 10.1002/advs.202403629. Epub 2024 Sep 26.
Certain metabolites in the tumor microenvironment (TME) can alter innate immunity. Here, it is shown how phosphomevalonate kinase (PMVK) allows hepatocellular carcinoma (HCC) cells to overcome the anti-tumor immunity mediated by CD8 T cells. In HCCs, depletion of PMVK is required to facilitate CD8 T cell activation and their subsequent suppression of tumor growth. Mechanistically, PMVK phosphorylates and stabilizes glutamate decarboxylase 1 (GAD1), thus increasing the synthesis of γ-aminobutyric acid (GABA), which normally functions as a neurotransmitter. However, PMVK also recruits acetyl-CoA acetyltransferase 1 (ACAT1) and allows it to convert GABA, to 4-acetaminobutyric acid (4-Ac-GABA), which is released into the TME. There, 4-Ac-GABA activates the GABAA receptor (GABAAR) on CD8 T cells, which inhibits AKT1 signaling. This in turn suppresses CD8 T cell activation, intratumoral infiltration, and the anti-tumor response. Inhibiting PMVK or GABAAR in HCC mouse models overcomes resistance to anti-PD-1 immune checkpoint therapy. These findings reveal non-canonical and cooperative functions among the key metabolic enzymes PMVK, GAD1, and ACAT1 that reprogram glutamine metabolism to synthesize a potent CD8 T cell inhibitor 4-Ac-GABA. Blocking 4-Ac-GABA signaling in CD8 T cells, particularly when combined with immune checkpoint inhibition, potentially represents a new and potent form of immunotherapy.
肿瘤微环境（TME）中的某些代谢物可以改变先天免疫。本文展示了磷酸甲羟戊酸激酶（PMVK）如何使肝细胞癌（HCC）细胞能够克服 CD8 T 细胞介导的抗肿瘤免疫。在 HCC 中，需要耗尽 PMVK 以促进 CD8 T 细胞的激活及其随后对肿瘤生长的抑制。从机制上讲，PMVK 磷酸化并稳定谷氨酸脱羧酶 1（GAD1），从而增加γ-氨基丁酸（GABA）的合成，GABA 通常作为神经递质发挥作用。然而，PMVK 还招募乙酰辅酶 A 乙酰转移酶 1（ACAT1）并允许其将 GABA 转化为 4-乙酰氨基丁酸（4-Ac-GABA），4-Ac-GABA 释放到 TME 中。在那里，4-Ac-GABA 激活 CD8 T 细胞上的 GABAA 受体（GABAAR），抑制 AKT1 信号。这反过来又抑制了 CD8 T 细胞的激活、肿瘤内浸润和抗肿瘤反应。在 HCC 小鼠模型中抑制 PMVK 或 GABAAR 可克服对抗 PD-1 免疫检查点治疗的耐药性。这些发现揭示了关键代谢酶 PMVK、GAD1 和 ACAT1 之间的非典型和协同功能，它们重新编程谷氨酰胺代谢以合成强效 CD8 T 细胞抑制剂 4-Ac-GABA。阻断 CD8 T 细胞中的 4-Ac-GABA 信号，特别是与免疫检查点抑制相结合，可能代表一种新的、有效的免疫疗法形式。
