Work

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

Year: 2019

Type: preprint

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.

Source: bioRxiv (Cold Spring Harbor Laboratory)

DOI: 10.1101/799759