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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 Article has an altmetric score of 16

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 6

Transcriptional regulation of gpx4 by E2F1.

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Transcriptional regulation of gpx4 by E2F1.
(A and B) GPX4 expression le...
(A and B) GPX4 expression level was evaluated by flow cytometry in activated WT and adora2afl/fl Lckcre cKO CD8+ T cells. (C) ATAC-seq analysis by Partek Flow software showing chromatin accessibility within the vicinity of transcribed regions for GPX4 in activated Pmel CD8+ T cells treated with or without A2ARi. (D) Predicted binding sites by PROMO-ALGGEN Web tool for human and mouse gpx4 by E2F1. (E) Correlation between gene expression levels of e2f1 and gpx4 by qRT-PCR in activated Pmel CD8+ T cells. (F and G) qRT-PCR was performed to detect expression levels of e2f1 in activated Pmel CD8+ T cells treated with or without A2ARi (F) or with or without H89 (G). (H) ATAC-seq analysis by Partek Flow showing chromatin accessibility within the vicinity of transcribed regions for E2F1 in activated Pmel CD8+ T cells treated with or without A2ARi. (I) ChIP-qPCR analysis confirming the binding capacity of E2F1 on gpx4 in activated control OT-1 CD8+ T cells rather than gpx4fl/fl CD4cre OT-1 CD8+ T cells. (J–L) Activated Pmel CD8+ T cells in the presence of gp100, anti-CD28, 5′-AMP, and cell-permeable GSH were treated with or without A2ARi, Lip-1, E2F1 inhibitor HLM 006474, or combination. On day 7, the percentages of viable (J), Ki67+ (K), and IFN-γ+ (L) T cells were measured. Results are representative of 2 (C, H, and I) or 3 (B, E–G, and J–L) independent experiments. Data were analyzed by Pearson’s correlation (E), 2-tailed t test (B, F, and G), and 2-way ANOVA (I–L). Data plotted are mean ± SEM from biological replicates. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.

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

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