CD8+ T cells sustain antitumor response by mediating crosstalk between adenosine A2A receptor and glutathione/GPX4

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-dependent (GPX4-dependent) ferr...

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Bibliographic Details
Published in:The Journal of clinical investigation 2024-04, Vol.134 (8), p.1-17
Main Authors: Chen, Siqi, Fan, Jie, Xie, Ping, Ahn, Jihae, Fernandez, Michelle, Billingham, Leah K, Miska, Jason, Wu, Jennifer D, Wainwright, Derek A, Fang, Deyu, Sosman, Jeffrey A, Wan, Yong, Zhang, Yi, Chandel, Navdeep S, Zhang, Bin
Format: Article
Language:English
Subjects:
Adenosine
Antigens
Antitumor activity
Cancer
CD8 antigen
CD8-Positive T-Lymphocytes - metabolism
Cell therapy
Cells
Ferroptosis
Fitness
Glutathione - metabolism
Glutathione peroxidase
Humans
Lipid peroxidation
Lipids
Lymphocytes
Lymphocytes T
Metabolism
Neoplasms - genetics
Neoplasms - metabolism
Neoplasms - therapy
Oxidative stress
Phospholipid Hydroperoxide Glutathione Peroxidase - metabolism
Receptor, Adenosine A2A - genetics
Receptor, Adenosine A2A - metabolism
Tumors
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Summary: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-dependent (GPX4-dependent) ferroptosis. Here, we show the necessity of adenosine A2A receptor (A2AR) signaling and the 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. 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.
ISSN:1558-8238
0021-9738
1558-8238
DOI:10.1172/JCI170071