postdoc research fellow Brigham and Women's Hospital, Harvard Medical School Boston, Massachusetts, United States
Disclosure(s):
Dandan Yang, PhD: No financial relationships to disclose
Introduction/Rationale: Glucocorticoids (GCs) are anti-inflammatory steroid hormones derived from cholesterol. Owing to their potent immunosuppressive activity, exogenous GCs are widely used to treat autoimmune/allergic inflammation and to manage immune-related adverse events (irAEs) during cancer immunotherapy. GCs signal through the glucocorticoid receptor (GR), a ligand-activated transcription factor encoded by Nr3c1. GR regulates gene expression both directly, by binding glucocorticoid response elements (GREs) in target loci, and indirectly, by transrepressing the activity of other transcription factors. We previously showed that endogenous GR signaling dynamically shapes the differentiation of CD8⁺ tumor-infiltrating lymphocytes (TILs) within the tumor microenvironment (TME); however, the mechanisms and key downstream effectors remain poorly defined.
Methods: To define GR-dependent regulatory networks in CD8⁺ T cells, we performed in vivo single-cell RNA sequencing of wild-type (WT) and GR-deficient CD8⁺ TILs. In parallel, we conducted time-resolved, bulk RNA-seq over 72 hours (six early and late time points) in GC-treated WT versus GR-deficient CD8⁺ T cells to identify GR-regulated candidate effectors. We then used CRISPR-Cas9 perturbation to validate the functions of prioritized targets in the TME.
Results: These analyses revealed that GR signaling diverts CD8⁺ T cell differentiation from effector and tissue-resident memory (TRM)-like lineages toward dysfunctional states unresponsive to immune checkpoint blockade (ICB). Mechanistically, GR signaling repressed glycolysis via TXNIP, thereby compromising the metabolic fitness of CD8⁺ T cells, limiting their clonal expansion, effector differentiation, and instead promoting dysfunctional phenotypes, ultimately attenuating anti-tumor immunity.
Conclusion: Together, our findings define a GR-TXNIP metabolic axis that directs the fate of CD8+ TILs and has important implications for the clinical use of exogenous glucocorticoids in patients receiving ICB.
