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

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 7

Identification of a tumor-infiltrating CD8+ T cell cluster expressing the GSH metabolism signature genes (GMSG) across a range of human cancers.

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Identification of a tumor-infiltrating CD8+ T cell cluster expressing th...
(A and B) Dot plot of scRNA-Seq data (https://singlecell.broadinstitute.org/single_cell) showing geometric mean expression (log[TP10K+1]) and frequency (dot size) of key genes associated with GSH metabolism in clusters of tumor-infiltrating CD3+ and/or CD8+ T cells from patients with breast cancer (n = 26), renal carcinoma (n = 8), melanoma (n = 59), and colon cancer (n = 62). Clusters enriched in GSH metabolism signature genes (GMSG) are indicated in bold green. (C) The GMSG-enriched tumor-infiltrating CD8+ T cell cluster was found only in ICB_PR renal carcinoma patients (SCP1288; n = 2). (D) Correlation between the score (normalized gene expression relative to the total of tumor-infiltrating CD8+ T cells for a curated list of GMSG) and overall survival of melanoma patients (SCP398; n = 27). (E) Scores of GMSG in MMRd (R) (n = 34) and MMRp (NR) (n = 28) colorectal cancer patients (SCP1162). (F) Representative composite image of a breast cancer specimen stained by multicolor IHC comprising CD8, Ki67, GCLC, GPX4, A2AR, PanCK, and DAPI. Scale bars: 10 μm. Original magnification, ×20. Representative CD8+GPX4+ (blue arrow), CD8+GCLC+ (blue arrowhead), CD8+GPX4+GCLC+ (red arrows), and CD8+Ki67+GPX4+GCLC+ (red arrowhead) cells. (G and H) Correlation between CD8+Ki67+ density and CD8+GPX4+ density (G) or CD8+GCLC+ density (H). (I and J) Intensity of GPX4 (I) or GCLC (J) was compared between CD8+Ki67+ cells and CD8+Ki67– cells among cases of invasive ductal carcinoma (IDC: G2, n = 27; G3, n = 24) and medullary carcinoma of the breast (MCB, n = 9) and normal breast tissues (n = 3). (K) Intensity of GCLC was compared between CD8+A2AR+ cells and CD8+A2AR– cells among cases of IDC (G2, n = 27; G3, n = 24) and MCB (n = 9) and normal breast tissues (n = 3). Data were analyzed by Pearson’s correlation (D, G, and H), 2-way ANOVA (I–K), and 2-sided Mann-Whitney test (E). *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.