谷氨酸受体
生物
细胞生物学
癌症研究
谷氨酰胺
神经递质
γ-氨基丁酸受体
谷氨酸脱羧酶
癌细胞
免疫抑制
癌症
受体
生物化学
免疫学
γ-氨基丁酸受体
氨基酸
酶
遗传学
作者
De Huang,Yan Wang,J. Will Thompson,Tao Yin,Peter Alexander,Diyuan Qin,Poorva Mudgal,Haiyang Wu,Yaosi Liang,Licheng Tan,Christopher C. Pan,Lifeng Yuan,Ying Wan,Qi-Jing Li,Xiao‐Fan Wang
标识
DOI:10.1038/s41556-021-00820-9
摘要
Many cancers have an unusual dependence on glutamine. However, most previous studies have focused on the contribution of glutamine to metabolic building blocks and the energy supply. Here, we report that cancer cells with aberrant expression of glutamate decarboxylase 1 (GAD1) rewire glutamine metabolism for the synthesis of γ-aminobutyric acid (GABA)-a prominent neurotransmitter-in non-nervous tissues. An analysis of clinical samples reveals that increased GABA levels predict poor prognosis. Mechanistically, we identify a cancer-intrinsic pathway through which GABA activates the GABAB receptor to inhibit GSK-3β activity, leading to enhanced β-catenin signalling. This GABA-mediated β-catenin activation both stimulates tumour cell proliferation and suppresses CD8+ T cell intratumoural infiltration, such that targeting GAD1 or GABABR in mouse models overcomes resistance to anti-PD-1 immune checkpoint blockade therapy. Our findings uncover a signalling role for tumour-derived GABA beyond its classic function as a neurotransmitter that can be targeted pharmacologically to reverse immunosuppression.
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