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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 4

Adoptive T cell therapy with A2ARi plus Lip-1.

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Adoptive T cell therapy with A2ARi plus Lip-1.
The percentages and/or nu...
The percentages and/or numbers of viable (A), Ki67+ (B and C), and IFN-γ+ (D and E) cells were measured in activated CD8+ T cells as indicated. The percentages of viable PD-1+Lag-3+ (F), CD44+TCF1+ (G), and CD44+CD127+ (H) cells were measured in activated CD8+ T cells as indicated. Percentages of PD-1+Lag-3+ (I), PD-1+CD39+ (J), Ly108+CD69+ (K), CD127+ (N), or CD127+GPX4+ (O) cells among transferred cells in EG7 tumor infiltrates (n = 5) were measured 1 week after i.v. transfer of activated OT-1 CD90.1+CD8+ T cells. In parallel, infiltrating transferred T cells were sorted and measured for intracellular GSH and GSSG by HPLC. The GSH/GSSG ratio was calculated (L). Lipid ROS levels indicated by BODIPY FITC were also detected in transferred infiltrating T cells by flow cytometry (M). Tumor volume (P) and survival (Q) were measured in MC38-bearing mice (n = 5) with and without i.v. transfer of activated tumor-reactive CD90.1+CD8+ T cells as indicated. (R and S) EG7-bearing mice (n = 5) received i.v. transfer of activated OT-1 CD90.1+CD8+ T cells as indicated. Mouse survival was measured until day 200 (R). Tumor-free mice from R were rechallenged with EG7 cells, while naive mice received the same EG7 cells simultaneously s.c., and mouse survival was measured over time (S). Tumor volume (T) and weight (U) (on day 28) were measured in HCC-1806–bearing mice (n = 4) with activated anti-MSLN CAR T cells as indicated. Results are representative of 2 (F–H and P–S) or 3 (A–E, T, and U) independent experiments. Data were analyzed by 2-way ANOVA (A, C, E, F–O, T, and U) and log-rank test for survival curves (Q and R). Data plotted are mean ± SEM from biological replicates. *P < 0.05, **P < 0.01, ***P < 0.001.

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