Tumors produce glucocorticoids by metabolite recycling, not synthesis, and activate Tregs to promote growth

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 11ß-HSD1 (encoded by Hsd11b1). Here we find 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 with increased frequencies of tumor-infiltrating CD8+ T cells (TIL) expressing activation markers and producing effector cytokines. Tumor-derived glucocorticoids were found to promote signatures of Treg activation and suppress signatures of Tconv activation in tumor-infiltrating Treg. Indeed, CD8+ T cell activation was restored and tumor growth reduced in mice with Treg-specific glucocorticoid receptor deficiency. Importantly, pharmacologic inhibition of 11ß-HSD1 reduced tumor growth to the same degree as gene knockout, and rendered immunotherapy-resistant tumors susceptible to PD-1 blockade. Given that HSD11B1 expression is upregulated in many human tumors and that inhibition of 11ß-HSD1 is well-tolerated in clinical studies, these data suggest that targeting 11ß-HSD1 may be a beneficial adjunct in cancer therapy. Overall design: B16.F10 mouse melanoma cells were implanted into Nr3c1-flox/flox and Nr3c1-flox/flox Foxp3-YFP/Cre recipient mice. Tumors were dissociated, Treg cells purified by FACS, total RNA extracted, and bulk RNA-seq performed by next generation sequencing.