串扰
谷胱甘肽
腺苷
细胞生物学
腺苷受体
腺苷A2A受体
化学
受体
生物
生物化学
物理
酶
光学
兴奋剂
作者
Siqi Chen,Jia Fan,Ping Xie,Jihae Ahn,Michelle Fernández,Leah K. Billingham,Jason Miska,Jennifer D. Wu,Derek A. Wainwright,Deyu Fang,Jeffrey A. Sosman,Yong Wan,Yi Zhang,Navdeep S. Chandel,Bin Zhang
摘要
Antitumor responses of CD8+ T cells are tightly regulated by distinct metabolic fitness. High levels of glutathione (GSH) are observed in the majority of tumors contributing to cancer progression and treatment resistance in part by preventing glutathione peroxidase 4 (GPX4) dependent ferroptosis. Here, we show the necessity of the adenosine A2A receptor (A2AR) signaling and the glutathione (GSH)-GPX4 axis in orchestrating metabolic fitness and survival of functionally competent CD8+ T cells. Activated CD8+ T cells treated ex vivo with simultaneous inhibition of A2AR and lipid peroxidation acquire a superior capacity to proliferate and persist in vivo, demonstrating a translatable means to prevent ferroptosis in adoptive cell therapy (ACT). Additionally, we identify a particular cluster of intratumoral CD8+ T cells expressing a putative gene signature of GSH metabolism (GMGS) in association with clinical response and survival across several human cancers. Our study addresses a key role of GSH-GPX4 and adenosinergic pathways in fine-tuning the metabolic fitness of antitumor CD8+ T cells.
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