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

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 5

Glucocorticoids suppress antitumor immunity by enhancing Treg function.

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Glucocorticoids suppress antitumor immunity by enhancing Treg function. ...
(A) B16 tumor growth in control or Nr3c1Foxp3-Cre mice (n = 10, 12). Representative of 6 experiments. (B) B16 tumor masses in control or Nr3c1Foxp3-Cre mice (n = 43, 37). Data pooled from 6 experiments. (C) Panc02 tumor growth in control or Nr3c1Foxp3-Cre mice (n = 6, 8). Representative of 2 experiments. (D) Panc02 tumor masses in control or Nr3c1Foxp3-Cre mice (n = 17, 17). Data pooled from 3 experiments. (E) Expression of miRNAs in FACS-sorted Tregs from B16 tumors implanted into control or Nr3c1Foxp3-Cre mice (n = 6, 6). Data pooled from 2 experiments. (F) Rictor expression in Tregs from B16 tumors of control or Nr3c1Foxp3-Cre mice (n = 4, 4). Tumor-infiltrating cells were isolated, stained, and analyzed by flow cytometry. Representative of 2 experiments. (G) Treg expression of CD39 in B16 tumors of control and Nr3c1Foxp3-Cre mice (n = 13, 13). Tumor-infiltrating cells were isolated, stained, and analyzed by flow cytometry. Data pooled from 3 experiments. (H) CD8+ T cell phenotypes in B16 tumors of control Nr3c1Foxp3-Cre mice (n = 8, 8). Tumor-infiltrating cells were isolated from tumors, stained, and analyzed by flow cytometry. Data pooled from 2 experiments. (I and J) Enrichment plots of genes upregulated (top) and downregulated (bottom) in GR-deficient versus control tumor-infiltrating Tregs compared with the gene set upregulated in activated Tconvs (CD4+Foxp3– T cells) versus activated natural Tregs (CD4+Foxp3+ T cells). (K and L) Relative expression of the top 20 genes in GR-deficient and control tumor-infiltrating Tregs that paralleled increased expression in activated Tconvs versus activated Tregs (K) or decreased expression in activated Tconvs versus activated Tregs (L). Tumor growth was analyzed using rmANOVA with mouse genotype and sex as factors. Tumor masses, cell gene expression, and protein expression were analyzed using ANOVA with mouse genotype, sex, and experiment as factors, except for data in F, which was analyzed with an unpaired t test. Data are represented as means ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001. Supporting data are available in Supplemental Figure 5.