ORF11-08 - Inhibition of T Cell-Intrinsic Glucocorticoid Production Enhances Tumor Immunity

Adrenal glucocorticoids act systemically to maintain physiological homeostasis, in part by potently suppressing immune responses. This immunosuppression can have major negative effects, including inhibition of tumor immunity and increased tumor progression and mortality. Recent work has discovered that various tumors can locally produce glucocorticoids via expression of the enzyme 11β-HSD1, which recycles active cortisol from inactive cortisone. This tumor-derived cortisol amplifies local immunosuppression, inhibiting tumor cell killing and promoting tumor growth. We have found that 11β-HSD1 is not limited to tumor cells but is also present in tumor-infiltrating T cells, suggesting that T cell-intrinsic glucocorticoid production may function as a novel inhibitory signal. To determine if T cell 11β-HSD1 is induced by activation we purified and stimulated T cells in vitro via the T cell antigen receptor. Upon activation, T cells increased 11β-HSD1 gene expression and enzyme activity, suggesting a role as a novel immune checkpoint. T cell-generated glucocorticoids furthermore upregulated expression of the surface inhibitory receptor PD-1. To examine whether immune cell 11β-HSD1 inhibits tumor immunity we then implanted mice with MC38 (colon carcinoma) or LLC (Lewis lung carcinoma) tumors, with minimal and no 11β-HSD1 activity, respectively, and administered vehicle or an 11β-HSD1 inhibitor (carbenoxolone or PF-915275, 50 mg/kg) daily. 11β-HSD1 inhibition reduced the growth of both MC38 and LLC tumors, consistent with inhibition of immune cell-intrinsic immunosuppressive glucocorticoid signaling. These findings indicate that T cell 11β-HSD1 regenerates active glucocorticoids that impair tumor immunity and promote tumor growth. Pharmacological inhibition of 11β-HSD1 may therefore be a useful immunotherapy for a wide range of tumors, independent of tumor cell 11β-HSD1 expression.