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

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

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 2

Inactivation of A2AR signaling orchestrates CD8+ T cell responses by coordinating the GSH/GPX4 axis.

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Inactivation of A2AR signaling orchestrates CD8+ T cell responses by coo...
(A) RNA-Seq was performed in activated Pmel CD8+ T cells treated with or without Lip-1. Heatmap shows enriched genes involved in the adenosine pathway. (B) qRT-PCR analysis of adora2a transcripts in activated CD8+ T cells. (C) Total GSH content including both reduced (GSH) and oxidized (GSSG) forms was measured in activated CD8+ T cells from indicated mice in vitro with HPLC. (D–G) Relative levels of indicated metabolites were measured by LC-MS in activated Pmel CD8+ T cells treated as indicated (D–F). The GSH/GSSG ratio was calculated (G). The percentages and/or numbers of viable (H), Ki67+ (I), and IFN-γ+ (J) cells were measured in activated gpx4fl/fl CD4cre OT-1 CD8+ T cells. (K and L) Flow cytometry analysis of ectopic GPX4 expression in activated WT CD8+ T cells. (M) Numbers of transferred CD8+IFN-γ+ cells were measured within MC38 tumors (n = 4) 14 days after i.v. transfer of activated CD90.1+CD8+ T cells with or without ectopic expression of GPX4. (N and O) Flow cytometry analysis of ectopic GCLC expression in activated OT-1 CD90.1+CD8+ T cells. (P) Numbers of transferred CD8+IFN-γ+ cells were analyzed within LLC1-OVA tumors (n = 8) 14 days after i.v. transfer of activated OT-1 CD90.1+CD8+ T cells with or without ectopic expression of GCLC. (Q) Tumor weights were also recorded. Results are representative of 2 (A, B, D–G, and K–Q) or 3 (C and H–J) independent experiments. Data were analyzed by 2-tailed t test (B, F, L, and O) and 2-way ANOVA (C, D, G, H–J, M, P, and Q). Data plotted are mean ± SEM from biological replicates. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.