18. Dandan Yang, PhD

CD8+ tumor-infiltrating lymphocytes (TIL) are pivotal for tumor elimination, yet suppressive signals within the tumor microenvironment (TME) disrupt their effector differentiation and foster a dysfunctional state. Uncovering these suppressive signals and their downstream effects is essential to enhancing CD8+ T cell responses against tumors. Our prior studies showed that endogenous glucocorticoid (GC) signaling within the TME alters CD8+ T cell effector differentiation trajectory but the mechanisms remained unclear. We have examined the cell state-specific RNA profiles of wild type (WT) and glucocorticoid receptor (GR)-deficient CD8+ TIL by single-cell RNA sequencing. Our findings reveal that GC signaling shifts the balance of CD8+ T cells differentiating along two distinct lineages, disfavoring differentiation along the lineage culminating in effector and tissue-resident memory (TRM)-like cells and favoring differentiation along the lineage culminating in dysfunctional states unresponsive to immune checkpoint therapies. Further analysis indicates that GC signaling alters CD8+ T cell differentiation along these lineages by altering their metabolism—specifically, inhibiting glycolysis and promoting fatty acid oxidation—thereby fostering dysfunctional states and inhibiting effector states, ultimately dampening anti-tumor immunity. Our findings provide insights into the impact of exogenous GC administration on CD8+ T cell responses, potentially guiding new strategies to enhance CD8+ T cell-mediated tumor clearance. Our data further have implications for the clinical administration of glucocorticoids in patients receiving immunotherapy.