An endogenous glucocorticoid-cytokine signaling circuit promotes CD8+ T cell dysfunction in the tumor microenvironment
Acharya, N.; Madi, A.; Zhang, H.; Klapholz, M.; Christian, E.; Dixon, K. O.; Fell, G.; Tooley, K.; Mangani, D.; Xia, J.; Singer, M.; Neuberg, D.; Rozenblatt-Rosen, O.; Regev, A.; Kuchroo, V. K.; Anderson, A. C.
Show 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.
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