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Tumors produce glucocorticoids by metabolite recycling, not synthesis, and activate Tregs to promote growth
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...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Clinical Investigation
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10503810/ https://www.ncbi.nlm.nih.gov/pubmed/37471141 http://dx.doi.org/10.1172/JCI164599 |
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author | Taves, Matthew D. Otsuka, Shizuka Taylor, Michaela A. Donahue, Kaitlynn M. Meyer, Thomas J. Cam, Margaret C. Ashwell, Jonathan D. |
author_facet | Taves, Matthew D. Otsuka, Shizuka Taylor, Michaela A. Donahue, Kaitlynn M. Meyer, Thomas J. Cam, Margaret C. Ashwell, Jonathan D. |
author_sort | Taves, Matthew D. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-10503810 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | American Society for Clinical Investigation |
record_format | MEDLINE/PubMed |
spelling | pubmed-105038102023-09-16 Tumors produce glucocorticoids by metabolite recycling, not synthesis, and activate Tregs to promote growth Taves, Matthew D. Otsuka, Shizuka Taylor, Michaela A. Donahue, Kaitlynn M. Meyer, Thomas J. Cam, Margaret C. Ashwell, Jonathan D. J Clin Invest Research Article 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. American Society for Clinical Investigation 2023-09-15 /pmc/articles/PMC10503810/ /pubmed/37471141 http://dx.doi.org/10.1172/JCI164599 Text en © 2023 Taves et al. https://creativecommons.org/licenses/by/4.0/This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Research Article Taves, Matthew D. Otsuka, Shizuka Taylor, Michaela A. Donahue, Kaitlynn M. Meyer, Thomas J. Cam, Margaret C. Ashwell, Jonathan D. Tumors produce glucocorticoids by metabolite recycling, not synthesis, and activate Tregs to promote growth |
title | Tumors produce glucocorticoids by metabolite recycling, not synthesis, and activate Tregs to promote growth |
title_full | Tumors produce glucocorticoids by metabolite recycling, not synthesis, and activate Tregs to promote growth |
title_fullStr | Tumors produce glucocorticoids by metabolite recycling, not synthesis, and activate Tregs to promote growth |
title_full_unstemmed | Tumors produce glucocorticoids by metabolite recycling, not synthesis, and activate Tregs to promote growth |
title_short | Tumors produce glucocorticoids by metabolite recycling, not synthesis, and activate Tregs to promote growth |
title_sort | tumors produce glucocorticoids by metabolite recycling, not synthesis, and activate tregs to promote growth |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10503810/ https://www.ncbi.nlm.nih.gov/pubmed/37471141 http://dx.doi.org/10.1172/JCI164599 |
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