Ovarian cancer cell glucocorticoid receptor activation increases myeloid-derived suppressor cell tumor infiltration

High ovarian cancer cell glucocorticoid receptor (GR) expression is associated with reduced progression-free survival (PFS) despite standard debulking surgery and adjuvant chemotherapy. Although not previously linked to tumor-cell GR expression, a "cold" (immune-suppressive) ovarian cancer tumor microenvironment (TME) is also associated with poor prognosis. In this study, analysis of The Cancer Genome Atlas (TCGA) ovarian cancer database revealed that NR3C1 (GR) mRNA was positively correlated with immunosuppressive cytokine gene expression. Higher tumor NR3C1 expression also associated with gene expression encoding cellular markers of immunosuppressive myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs). In vitro, GR activation in human and mouse ovarian cancer cell lines led to increased secretion of pro-tumorigenic cytokines, including G-CSF, M-CSF, TGFβ2, and CXCL2. Co-treatment with a GR agonist (mimicking endogenous cortisol) and a selective GR modulator (SGRM) significantly reduced cytokine secretion. In human xenograft mouse models, systemic administration of a SGRM decreased serum immunosuppressive cytokine concentrations and mouse MDSC tumor infiltration, suggesting that tumor-cell GR activity and cytokine secretion contribute to MDSC generation and recruitment. Additionally, in a syngeneic model of GR-positive ovarian cancer, both pharmacologic GR antagonism and tumor cell-specific GR knockdown reduced intratumoral and circulating MDSCs, as well as intratumoral Tregs. Collectively, these findings suggest that ovarian cancer-cell GR activity contributes to maintaining a highly immunosuppressive TME through secretion of tumor-derived cytokines. We conclude that ovarian cancer cell GR activity has a previously unrecognized role in inhibiting anti-tumor immunity and that systemic GR modulation could improve immunotherapy outcomes in ovarian cancer.