Abstract 5863: Blockade of tumor glucocorticoid production inhibits Treg function and tumor growth

Abstract

Abstract Glucocorticoids (GCs) are steroid hormones with potent immunosuppressive properties. GCs are primary produced from cholesterol in the adrenals via the de novo synthetic pathway. In some tissues, however, there is also a recycling pathway in which the enzyme 11β-HSD1 generates GCs from the inactive metabolites dehydrocorticosterone (rodent) or cortisone (human). Here we find that multiple tumor types produce GCs via 11β-HSD1 in vitro and in vivo. We used CRISPR/Cas9 technology to knock out Hsd11b1 in GC-producing tumor cell lines and found that lack of 11β-HSD1 in B16 melanoma, Panc02 pancreatic adenocarcinoma, and MC38 colon carcinoma lines reduced their growth in vivo. Reduced tumor growth corresponded with increased expression of the activation marker CD44 and production of the effector cytokines IFNγ and TNFα by tumor-infiltrating CD8+ T cells (TILs). Rather than directly suppressing effector cell function, recent findings have suggested that GCs instead act primarily by activating Treg cells, and that these Treg are responsible for inhibition of effector cell function. Consistent with this, we found that tumor-derived GCs upregulate Treg expression of miRNA-342, which downregulates the mTOR component Rictor and activates Treg activity. A role of tumor-derived GCs in enhancing Treg function was demonstrated by inoculating tumor cells into mice with Treg-specific glucocorticoid receptor deficiency (GRFoxp3Cre mice). Notably, growth of tumors was reduced in GRFoxp3Cre mice, along with increased CD8+ TIL activation. Importantly, pharmacologic inhibition of 11β-HSD1 reduced WT tumor growth to the same degree as knockout of 11β-HSD1, and rendered immunotherapy-resistant tumors susceptible to inhibition with anti-PD-1 antibodies. Given that 11β-HSD1 expression is upregulated in many human tumors, these data suggest that its inhibition, which has been accomplished in a number of phase 3 clinical trials for other indications and is well-tolerated, may be beneficial in their treatment. Citation Format: Shizuka Otsuka, Matthew D. Taves, Kaitlynn M. Donahue, Jonathan D. Ashwell. Blockade of tumor glucocorticoid production inhibits Treg function and tumor growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5863.