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.
| Original language | English (US) |
|---|---|
| Article number | e170071 |
| Journal | Journal of Clinical Investigation |
| Volume | 134 |
| Issue number | 8 |
| DOIs | |
| State | Published - Apr 15 2024 |
Funding
This research was supported in part by National Institutes of Health (NIH) grants CA222963 and CA250101, a Melanoma Research Alliance Foundation established investigator award, and a Chicago Biomedical Consortium Catalyst Award to BZ; NIH CA257520 to DF and BZ; and CA258857 to YW and BZ. Metabolomics services were performed by the Metabolomics Core Facility, immune characterization by the Immunotherapy Assessment Core Facility, and sequencing by the NUSeq Core Facility at Robert H. Lurie Comprehensive Cancer Center of Northwestern University with a Cancer Center Support Grant (National Cancer Institute CA060553).
ASJC Scopus subject areas
- General Medicine
