An endogenous glucocorticoid-cytokine signaling circuit promotes CD8+ T cell dysfunction in the tumor microenvironment

Abstract

Abstract

Identifying signals in the tumor microenvironment (TME) that promote CD8⁺ T cell dysfunction can inform improved therapeutic approaches for cancer. Here, we identify that Nr3c1, the gene encoding the glucocorticoid receptor (GR), is highly expressed in dysfunctional CD8⁺ tumor-infiltrating lymphocytes (TILs). The GR transactivates expression of multiple checkpoint receptors and loss of GR in CD8⁺ T cells limits dysfunctional phenotype in CD8⁺ TILs resulting in improved tumor growth control. We show that glucocorticoids can be produced in the TME and that they co-operate with the immunosuppressive cytokine IL-27 to promote the dysfunction gene program in CD8⁺ T cells. The presence of the glucocorticoid + IL27 signature in CD8⁺ TILs correlates with failure to respond to checkpoint blockade in melanoma patients, highlighting the relevance of this immunoregulatory glucocorticoid-cytokine circuit in tumor tissue.