Activation of endogenous glucocorticoids by HSD11B1 inhibits the antitumor immune response in renal cancer
Although immune-based therapies have revolutionized the management of cancer, novel approaches are urgently needed to improve their outcome. We investigated the role of endogenous steroids in the resistance to cancer immunotherapy, as these have strong immunomodulatory functions. Using a publicly av...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Taylor & Francis Group
2024-12-01
|
| Series: | OncoImmunology |
| Subjects: | |
| Online Access: | https://www.tandfonline.com/doi/10.1080/2162402X.2023.2286820 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1846142264572641280 |
|---|---|
| author | Hélène Poinot Eloïse Dupuychaffray Grégoire Arnoux Montserrat Alvarez Jérémie Tachet Ounss Ezzar Jonathan Moore Olivia Bejuy Eulalia Olesti Gioele Visconti Víctor González-Ruiz Serge Rudaz Jean-Christophe Tille Clarissa D. Voegel Patrycja Nowak-Sliwinska Carole Bourquin Aurélien Pommier |
| author_facet | Hélène Poinot Eloïse Dupuychaffray Grégoire Arnoux Montserrat Alvarez Jérémie Tachet Ounss Ezzar Jonathan Moore Olivia Bejuy Eulalia Olesti Gioele Visconti Víctor González-Ruiz Serge Rudaz Jean-Christophe Tille Clarissa D. Voegel Patrycja Nowak-Sliwinska Carole Bourquin Aurélien Pommier |
| author_sort | Hélène Poinot |
| collection | DOAJ |
| description | Although immune-based therapies have revolutionized the management of cancer, novel approaches are urgently needed to improve their outcome. We investigated the role of endogenous steroids in the resistance to cancer immunotherapy, as these have strong immunomodulatory functions. Using a publicly available database, we found that the intratumoral expression of 11 beta-hydroxysteroid dehydrogenase type 1 (HSD11B1), which regenerates inactive glucocorticoids into active glucocorticoids, was associated with poor clinical outcome and correlated with immunosuppressive gene signatures in patients with renal cell carcinoma (RCC). HSD11B1 was mainly expressed in tumor-infiltrating immune myeloid cells as seen by immunohistochemistry in RCC patient samples. Using peripheral blood mononuclear cells from healthy donors or immune cells isolated from the tumor of RCC patients, we showed that the pharmacological inhibition of HSD11B1 improved the response to the immune checkpoint inhibitor anti-PD-1. In a subcutaneous mouse model of renal cancer, the combination of an HSD11B1 inhibitor with anti-PD-1 treatment increased the proportion of tumor-infiltrating dendritic cells. In an intrarenal mouse tumor model, HSD11B1 inhibition increased the survival of mice treated with anti-PD-1. In addition, inhibition of HSD11B1 sensitized renal tumors in mice to immunotherapy with resiquimod, a Toll-like receptor 7 agonist. Mechanistically, we demonstrated that HSD11B1 inhibition combined with resiquimod increased T cell-mediated cytotoxicity to tumor cells by stimulating the antigen-presenting capacity of dendritic cells. In conclusion, these results support the use of HSD11B1 inhibitors to improve the outcome of immunotherapy in renal cancer and highlight the role of the endogenous glucocorticoid metabolism in the efficacy of immunotherapy. |
| format | Article |
| id | doaj-art-419652ef65f04df7a05ec68d586aacf1 |
| institution | Kabale University |
| issn | 2162-402X |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | OncoImmunology |
| spelling | doaj-art-419652ef65f04df7a05ec68d586aacf12024-12-03T13:49:34ZengTaylor & Francis GroupOncoImmunology2162-402X2024-12-0113110.1080/2162402X.2023.2286820Activation of endogenous glucocorticoids by HSD11B1 inhibits the antitumor immune response in renal cancerHélène Poinot0Eloïse Dupuychaffray1Grégoire Arnoux2Montserrat Alvarez3Jérémie Tachet4Ounss Ezzar5Jonathan Moore6Olivia Bejuy7Eulalia Olesti8Gioele Visconti9Víctor González-Ruiz10Serge Rudaz11Jean-Christophe Tille12Clarissa D. Voegel13Patrycja Nowak-Sliwinska14Carole Bourquin15Aurélien Pommier16School of Pharmaceutical Sciences, University of Geneva, Geneva, SwitzerlandSchool of Pharmaceutical Sciences, University of Geneva, Geneva, SwitzerlandDepartment of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, SwitzerlandSchool of Pharmaceutical Sciences, University of Geneva, Geneva, SwitzerlandSchool of Pharmaceutical Sciences, University of Geneva, Geneva, SwitzerlandSchool of Pharmaceutical Sciences, University of Geneva, Geneva, SwitzerlandTranslational Research Centre in Oncohaematology, Faculty of Medicine, University of Geneva, Geneva, SwitzerlandCIBM Center for Biomedical Imaging, Faculty of Medicine, University of Geneva, Geneva, SwitzerlandSchool of Pharmaceutical Sciences, University of Geneva, Geneva, SwitzerlandSchool of Pharmaceutical Sciences, University of Geneva, Geneva, SwitzerlandSchool of Pharmaceutical Sciences, University of Geneva, Geneva, SwitzerlandSchool of Pharmaceutical Sciences, University of Geneva, Geneva, SwitzerlandDivision of Clinical Pathology, Geneva University Hospitals, Geneva, SwitzerlandDepartment of Nephrology and Hypertension, Inselspital, Bern University Hospital, University of Bern, Bern, SwitzerlandSchool of Pharmaceutical Sciences, University of Geneva, Geneva, SwitzerlandSchool of Pharmaceutical Sciences, University of Geneva, Geneva, SwitzerlandSchool of Pharmaceutical Sciences, University of Geneva, Geneva, SwitzerlandAlthough immune-based therapies have revolutionized the management of cancer, novel approaches are urgently needed to improve their outcome. We investigated the role of endogenous steroids in the resistance to cancer immunotherapy, as these have strong immunomodulatory functions. Using a publicly available database, we found that the intratumoral expression of 11 beta-hydroxysteroid dehydrogenase type 1 (HSD11B1), which regenerates inactive glucocorticoids into active glucocorticoids, was associated with poor clinical outcome and correlated with immunosuppressive gene signatures in patients with renal cell carcinoma (RCC). HSD11B1 was mainly expressed in tumor-infiltrating immune myeloid cells as seen by immunohistochemistry in RCC patient samples. Using peripheral blood mononuclear cells from healthy donors or immune cells isolated from the tumor of RCC patients, we showed that the pharmacological inhibition of HSD11B1 improved the response to the immune checkpoint inhibitor anti-PD-1. In a subcutaneous mouse model of renal cancer, the combination of an HSD11B1 inhibitor with anti-PD-1 treatment increased the proportion of tumor-infiltrating dendritic cells. In an intrarenal mouse tumor model, HSD11B1 inhibition increased the survival of mice treated with anti-PD-1. In addition, inhibition of HSD11B1 sensitized renal tumors in mice to immunotherapy with resiquimod, a Toll-like receptor 7 agonist. Mechanistically, we demonstrated that HSD11B1 inhibition combined with resiquimod increased T cell-mediated cytotoxicity to tumor cells by stimulating the antigen-presenting capacity of dendritic cells. In conclusion, these results support the use of HSD11B1 inhibitors to improve the outcome of immunotherapy in renal cancer and highlight the role of the endogenous glucocorticoid metabolism in the efficacy of immunotherapy.https://www.tandfonline.com/doi/10.1080/2162402X.2023.2286820GlucocorticoidsHSD11B1immunotherapyrenal cancersteroidogenesis |
| spellingShingle | Hélène Poinot Eloïse Dupuychaffray Grégoire Arnoux Montserrat Alvarez Jérémie Tachet Ounss Ezzar Jonathan Moore Olivia Bejuy Eulalia Olesti Gioele Visconti Víctor González-Ruiz Serge Rudaz Jean-Christophe Tille Clarissa D. Voegel Patrycja Nowak-Sliwinska Carole Bourquin Aurélien Pommier Activation of endogenous glucocorticoids by HSD11B1 inhibits the antitumor immune response in renal cancer OncoImmunology Glucocorticoids HSD11B1 immunotherapy renal cancer steroidogenesis |
| title | Activation of endogenous glucocorticoids by HSD11B1 inhibits the antitumor immune response in renal cancer |
| title_full | Activation of endogenous glucocorticoids by HSD11B1 inhibits the antitumor immune response in renal cancer |
| title_fullStr | Activation of endogenous glucocorticoids by HSD11B1 inhibits the antitumor immune response in renal cancer |
| title_full_unstemmed | Activation of endogenous glucocorticoids by HSD11B1 inhibits the antitumor immune response in renal cancer |
| title_short | Activation of endogenous glucocorticoids by HSD11B1 inhibits the antitumor immune response in renal cancer |
| title_sort | activation of endogenous glucocorticoids by hsd11b1 inhibits the antitumor immune response in renal cancer |
| topic | Glucocorticoids HSD11B1 immunotherapy renal cancer steroidogenesis |
| url | https://www.tandfonline.com/doi/10.1080/2162402X.2023.2286820 |
| work_keys_str_mv | AT helenepoinot activationofendogenousglucocorticoidsbyhsd11b1inhibitstheantitumorimmuneresponseinrenalcancer AT eloisedupuychaffray activationofendogenousglucocorticoidsbyhsd11b1inhibitstheantitumorimmuneresponseinrenalcancer AT gregoirearnoux activationofendogenousglucocorticoidsbyhsd11b1inhibitstheantitumorimmuneresponseinrenalcancer AT montserratalvarez activationofendogenousglucocorticoidsbyhsd11b1inhibitstheantitumorimmuneresponseinrenalcancer AT jeremietachet activationofendogenousglucocorticoidsbyhsd11b1inhibitstheantitumorimmuneresponseinrenalcancer AT ounssezzar activationofendogenousglucocorticoidsbyhsd11b1inhibitstheantitumorimmuneresponseinrenalcancer AT jonathanmoore activationofendogenousglucocorticoidsbyhsd11b1inhibitstheantitumorimmuneresponseinrenalcancer AT oliviabejuy activationofendogenousglucocorticoidsbyhsd11b1inhibitstheantitumorimmuneresponseinrenalcancer AT eulaliaolesti activationofendogenousglucocorticoidsbyhsd11b1inhibitstheantitumorimmuneresponseinrenalcancer AT gioelevisconti activationofendogenousglucocorticoidsbyhsd11b1inhibitstheantitumorimmuneresponseinrenalcancer AT victorgonzalezruiz activationofendogenousglucocorticoidsbyhsd11b1inhibitstheantitumorimmuneresponseinrenalcancer AT sergerudaz activationofendogenousglucocorticoidsbyhsd11b1inhibitstheantitumorimmuneresponseinrenalcancer AT jeanchristophetille activationofendogenousglucocorticoidsbyhsd11b1inhibitstheantitumorimmuneresponseinrenalcancer AT clarissadvoegel activationofendogenousglucocorticoidsbyhsd11b1inhibitstheantitumorimmuneresponseinrenalcancer AT patrycjanowaksliwinska activationofendogenousglucocorticoidsbyhsd11b1inhibitstheantitumorimmuneresponseinrenalcancer AT carolebourquin activationofendogenousglucocorticoidsbyhsd11b1inhibitstheantitumorimmuneresponseinrenalcancer AT aurelienpommier activationofendogenousglucocorticoidsbyhsd11b1inhibitstheantitumorimmuneresponseinrenalcancer |