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

By Nandini Acharya, Asaf Madi, Huiyuan Zhang, Max Klapholz, Elena Christian, Karen O. Dixon, Geoffrey Fell, Katherine Tooley, Davide Mangani, Junrong Xia, Meromit Singer, Donna Neuberg, Orit Rozenblatt-Rosen, Aviv Regev, Vijay K Kuchroo, Ana C Anderson

Posted 10 Oct 2019
bioRxiv DOI: 10.1101/799759

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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