TY - JOUR T1 - An endogenous glucocorticoid-cytokine signaling circuit promotes CD8<sup>+</sup> T cell dysfunction in the tumor microenvironment JF - bioRxiv DO - 10.1101/799759 SP - 799759 AU - Nandini Acharya AU - Asaf Madi AU - Huiyuan Zhang AU - Max Klapholz AU - Elena Christian AU - Karen O. Dixon AU - Geoffrey Fell AU - Katherine Tooley AU - Davide Mangani AU - Junrong Xia AU - Meromit Singer AU - Donna Neuberg AU - Orit Rozenblatt-Rosen AU - Aviv Regev AU - Vijay K. Kuchroo AU - Ana C. Anderson Y1 - 2019/01/01 UR - http://biorxiv.org/content/early/2019/10/10/799759.abstract N2 - 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. ER -