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Tumors produce glucocorticoids by metabolite recycling, not synthesis, and activate Tregs to promote growth
Matthew D. Taves, … , Margaret C. Cam, Jonathan D. Ashwell
Matthew D. Taves, … , Margaret C. Cam, Jonathan D. Ashwell
Published July 20, 2023
Citation Information: J Clin Invest. 2023;133(18):e164599. https://doi.org/10.1172/JCI164599.
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Research Article Immunology Oncology Article has an altmetric score of 12

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

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Abstract

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-hydroxysteroid dehydrogenase type 1 (11β-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 CD8+ tumor-infiltrating lymphocytes (TILs) expressing activation markers and producing effector cytokines. Tumor-derived glucocorticoids were found to promote signatures of Treg activation and suppress signatures of conventional T cell activation in tumor-infiltrating Tregs. Indeed, CD8+ T cell activation was restored and tumor growth reduced in mice with Treg-specific glucocorticoid receptor deficiency. Importantly, pharmacologic inhibition of 11β-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 11β-HSD1 is well tolerated in clinical studies, these data suggest that targeting 11β-HSD1 may be a beneficial adjunct in cancer therapy.

Authors

Matthew D. Taves, Shizuka Otsuka, Michaela A. Taylor, Kaitlynn M. Donahue, Thomas J. Meyer, Margaret C. Cam, Jonathan D. Ashwell

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Figure 7

Pharmacological inhibition of 11β-HSD1 reduces tumor growth.

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Pharmacological inhibition of 11β-HSD1 reduces tumor growth.
(A) Inhibit...
(A) Inhibition of glucocorticoid generation by carbenoxolone and PF-915275. (B) B16 tumor growth in WT mice treated daily (beginning 24 hours after implant) with 50 mg/kg carbenoxolone or PBS (200 μL subcutaneous) (n = 3, 4). Representative of 2 experiments. (C) B16 tumor masses in PBS- or carbenoxolone-treated mice (n = 8, 7). Data pooled from 2 experiments. (D) B16 tumor growth in mice treated daily with 50 mg/kg PF-915275 or vehicle (200 μL subcutaneous) (n = 4, 4). Representative of 2 experiments. (E) B16 tumor masses in vehicle- or PF-915275–treated mice (n = 7, 7). Data pooled from 2 experiments. (F) Corticosterone production by 5 × 104 M1, M4, or M3 mouse melanoma cells cultured 45 minutes with 100 μM carbenoxolone and then overnight with 100 nM DOC or DHC. Corticosterone in supernatants was quantified via immunoassay. Data show duplicate samples and are representative of 2 experiments. (G) RNA-Seq data from M1, M4, and M3 cells (n = 9, 12, 11 samples) (51) analyzed for relative Hsd11b1 expression. (H) M3 tumor growth in mice treated daily with 50 mg/kg PF-915275 or vehicle (200 μL subcutaneous) (n = 4, 4). Representative of 2 experiments. (I) M3 tumor growth in WT mice treated with 6.25 mg/kg carbenoxolone or vehicle (50 μL intratumoral) (n = 7, 7) every 2 days (beginning day 9) for a total of 5 treatments. Representative of 2 experiments. (J) M3 tumor growth in mice treated daily with 6.25 mg/kg carbenoxolone or vehicle (200 μL subcutaneous) and treated with 10 mg/kg anti–PD-1 or rat IgG2a isotype control (200 μL intraperitoneal). Vehicle/isotype, n = 10; vehicle/anti–PD-1, n = 10; carbenoxolone/isotype, n = 12; carbenoxolone anti–PD-1, n = 10 mice. Tumor growth was analyzed using rmANOVA with treatment and sex as factors. Tumor masses were analyzed using ANOVA with treatment, sex, and experiment as factors. Data are shown as mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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