Article Impact Level: HIGH Data Quality: STRONG Summary of Endocrinology https://doi.org/10.1210/endocr/bqag019 Dr. Manisha Taya et al.
Points
- High expression of the glucocorticoid receptor in ovarian cancer cells is significantly correlated with shortened progression-free survival and increased resistance to standard adjuvant chemotherapy treatments.
- Analysis of international genomic databases revealed that the gene is positively linked to the expression of immunosuppressive cytokines that recruit regulatory T cells.
- Activating this specific receptor causes tumor cells to release biochemical signals that recruit myeloid-derived suppressor cells which effectively shut down local antitumor immune responses.
- Pharmacological inhibition of the receptor using the antagonist drug relacorilant successfully decreased suppressive cell infiltration and increased the recruitment of cancer-fighting immune cells.
- These findings provide a strong clinical rationale for combining glucocorticoid receptor antagonists with immunotherapies to transform immunologically cold ovarian tumors into active targets.
Summary
This study evaluated the molecular pathways by which tumor cell glucocorticoid receptor (GR) expression drives an immune-suppressive tumor microenvironment (TME) in ovarian cancer. Most ovarian malignancies present as immunologically “cold” tumors, but the primary upstream mechanisms maintaining this phenotype have been poorly characterized. Utilizing data from The Cancer Genome Atlas (TCGA) alongside murine and human ovarian cancer models, researchers sought to determine if elevated GR activation correlates with shortened progression-free survival (PFS) despite standard cytoreductive debulking surgery and platinum-based adjuvant chemotherapy.
Analysis of the TCGA ovarian database revealed that $NR3C1$ (GR) mRNA transcription positively correlates with enhanced expression of immunosuppressive cytokine genes. High tumor $NR3C1$ expression was also associated with gene profiles encoding specific surface markers for regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs). Mechanistically, intracellular GR activation forces the release of chemokinetic signals that preferentially recruit these suppressive cells into the TME. These recruited populations effectively silence local cytotoxic lymphocyte activity, leading to poor prognosis and chemoresistance in platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancers.
Conversely, targeted pharmacological inhibition using the GR antagonist relacorilant, or genetic ablation of the receptor, significantly down-regulated these suppressive chemical signals. This intervention decreased MDSC and Treg infiltration while concurrently enhancing the recruitment of active anti-tumor effector cells. The findings suggest that GR activity serves as a primary driver of TME evasion and chemoresistance, providing a mechanistic rationale for combining GR antagonists with cytotoxic agents like nab-paclitaxel or novel immunotherapies. Future prospective clinical trials are warranted to define specific hazard ratios for progression-free survival under these combined modalities.
Link to the article: https://academic.oup.com/endo/article-abstract/167/4/bqag019/8495721?redirectedFrom=fulltext&login=false
References
Taya, M., Gray, E., Srivastava, T., Chee, W.-Y., Fleming, G. F., DeVilbiss, A. W., Bennett, L. B., & Conzen, S. D. (2026). Ovarian cancer cell glucocorticoid receptor activation increases myeloid-derived suppressor cell tumor infiltration. Endocrinology, 167(4), bqag019. https://doi.org/10.1210/endocr/bqag019
