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

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

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 2

11β-HSD1 expression by cancer cells promotes tumor growth in vivo.

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11β-HSD1 expression by cancer cells promotes tumor growth in vivo. (A) B...
(A) B16 control and Hsd11b1–/– cell corticosterone generation in vitro after overnight incubation with 100 nM DHC. Representative of 2 independent experiments. (B) B16 control and Hsd11b1–/– cell tumor growth in WT mice (n = 8, 9). Representative of 7 experiments. (C) B16 control and Hsd11b1–/– cell tumor masses (n = 37, 37). Pooled from 7 experiments. (D) B16 control and Hsd11b1–/– cell growth in vitro after 72 hours in standard growth medium or supplemented with 100 nM DHC or corticosterone. (E) B16 control and Nr3c1–/– cell tumor growth in WT mice (n = 11, 12). Representative of 2 experiments. (F–H) Panc02 control and Hsd11b1–/– cell corticosterone generation in vitro, tumor growth (n = 8, 6; representative of 2 experiments), and tumor masses (n = 15, 12; pooled from 2 experiments). (I–K) MC38 control and Hsd11b1–/– cell corticosterone generation in vitro, tumor growth (n = 6, 7; representative of 2 experiments), and tumor masses (n = 12, 11; pooled from 2 experiments). (L–N) MC38 control and Hsd11b1Tg cell corticosterone generation in vitro, tumor growth (n = 8, 6; representative of 2 experiments), and tumor masses (n = 16, 14; pooled from 2 experiments). Tumor growth was analyzed using repeated-measures ANOVA (rmANOVA) with cell genotype and mouse sex as factors. Tumor mass was analyzed using ANOVA with cell genotype, mouse sex, and experiment as factors. Tumor data are represented as means ± SEM. *P < 0.05;**P < 0.01; ***P < 0.001. Supporting data are available in Supplemental Figure 2.