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CD8+ T cells sustain antitumor response by mediating crosstalk between adenosine A2A receptor and glutathione/GPX4
Siqi Chen, … , Navdeep S. Chandel, Bin Zhang
Siqi Chen, … , Navdeep S. Chandel, Bin Zhang
Published March 5, 2024
Citation Information: J Clin Invest. 2024;134(8):e170071. https://doi.org/10.1172/JCI170071.
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Research Article Immunology Metabolism

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

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Abstract

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.

Authors

Siqi Chen, Jie Fan, Ping Xie, Jihae Ahn, Michelle Fernandez, 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

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Figure 5

Combination of Lip-1 and A2ARi promotes mitochondrial function in activated CD8+ T cells.

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Combination of Lip-1 and A2ARi promotes mitochondrial function in activa...
(A–D) Activated OT-1 CD8+ T cells in the presence of OVA-I, anti-CD28, and GSH were treated with or without Lip-1, A2ARi, or a combination of both. RNA-Seq was performed in activated T cells, and GSEA plot showed the enriched pathway of oxidative phosphorylation in the combination of both compared with single treatment alone (A). Activated CD8+ T cells were fixed and observed by transmission electron microscopy (B). The number (C) and length (D) of cristae in mitochondria were measured and summarized. (E and F) Activated CD8+ T cells were stained with MTR and MTG to measure the mitochondrial membrane potential and mitochondrial mass, respectively (E). The ratio of MTRhiMTGlo to MTRloMTGhi was calculated (F). (G and H) The oxygen consumption rate (OCR) of activated OT-1 CD8+ T cells treated as indicated in the presence of OVA-I, anti-CD28, and GSH under normoxic (N) or hypoxic (H) conditions was measured by the Seahorse MitoStress Test with injections of oligomycin, FCCP, and antimycin A/rotenone (G). Basal OCR (H) was calculated from these activated CD8+ T cells cultured under hypoxic conditions. (I and J) Activated CD8+ T cells were stained with BODIPY and mBBr to measure neutral lipid by PE signal and GSH, respectively (I). The ratio of PEhiGSHhi to PEloGSHlo was calculated (J). Results are representative of 2 (A–D) or 3 (E, F, I, and J) independent experiments. Data were analyzed by 2-way ANOVA (C, D, F, H, and J). Data plotted are mean ± SEM from biological replicates. *P < 0.05, **P < 0.01, ***P < 0.001.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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