THU481 Glucocorticoid Regeneration By Tumor Cells Promotes Growth By Enhancing Regulatory T Cell Immunosuppression

Abstract

Abstract Disclosure: M.D. Taves: None. S. Otsuka: None. M.A. Taylor: None. K.M. Donahue: None. J.D. Ashwell: None. Glucocorticoids are steroid hormones with potent immunosuppressive properties. Their primary source is the adrenals, where they are generated via de novo synthesis from cholesterol. In addition, many tissues have a recycling pathway in which glucocorticoids are regenerated from inactive metabolites by the enzyme 11β-HSD1 (encoded by Hsd11b1). We found that multiple tumor types express Hsd11b1 and produce active glucocorticoids. Genetic ablation of Hsd11b1 in such cells had no effect on in vitro growth but reduced in vivo tumor progression, which corresponded to increased frequencies of tumor-infiltrating cytotoxic T cells expression activation markers and producing effector cytokines. Tumor-derived glucocorticoids upregulated tumor-infiltrating regulatory T cell (Treg) expression of miRNA-342 and downregulated the mTORC2 component Rictor, enhancing Treg activity. Indeed, cytotoxic T cell activation was restored and tumor growth reduced in mice with Treg-specific glucocorticoid receptor deficiency. Importantly, pharmacological inhibition of 11β-HSD1 reduced tumor growth to the same degree as gene knockout, and rendered immunotherapy-resistant tumors susceptible to immune checkpoint blockade. Given that HSD11B1 is upregulated in many human tumors and that inhibition of 11β-HSD1 is well-tolerated in clinical studies, these data suggest that targeting 11β-HSD1 may be a beneficial adjunct in cancer therapy. Presentation: Thursday, June 15, 2023