Activation of endogenous glucocorticoids by HSD11B1 inhibits the antitumor immune response in renal cancer

Article Article scientifique Article Activation of endogenous glucocorticoids by HSD11B1 inhibits the antitumor immune response in renal cancer eng 2023-11-30 2023-11-30 author Poinot Hélène 0009-0006-8347-8430 School of Pharmaceutical Sciences, University of Geneva, Geneva, Switzerland 894109 Département de physiologie cellulaire et métabolisme (PHYME) author Dupuychaffray Eloise 0009-0004-0465-6856 School of Pharmaceutical Sciences, University of Geneva, Geneva, Switzerland 884169 Section des sciences pharmaceutiques (FARMA) author Arnoux Grégoire Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland 674746 author Alvarez Montserrat 0000-0001-7206-073X School of Pharmaceutical Sciences, University of Geneva, Geneva, Switzerland 540586 Département de Pédiatrie, Gynécologie et Obstétrique (PETRI) author Tachet Jérémie 0000-0002-2442-6327 School of Pharmaceutical Sciences, University of Geneva, Geneva, Switzerland 851890 author Ezzar Ounss School of Pharmaceutical Sciences, University of Geneva, Geneva, Switzerland 815171 author Moore Jonathan 0000-0002-7586-671X Translational Research Centre in Oncohaematology, Faculty of Medicine, University of Geneva, Geneva, Switzerland 949979 author Bejuy Olivia 0000-0002-6457-6717 CIBM Center for Biomedical Imaging, Faculty of Medicine, University of Geneva, Geneva, Switzerland 800844 Centre d'imagerie bio-médicale (CIBM) author Olesti Eulalia 0000-0001-8677-9964 School of Pharmaceutical Sciences, University of Geneva, Geneva, Switzerland 918697 author Visconti Gioele 0000-0003-2486-7744 School of Pharmaceutical Sciences, University of Geneva, Geneva, Switzerland 783805 author Gonzalez Ruiz Victor 0000-0001-7204-2363 School of Pharmaceutical Sciences, University of Geneva, Geneva, Switzerland 831974 author Rudaz Serge 0000-0002-4180-5417 School of Pharmaceutical Sciences, University of Geneva, Geneva, Switzerland 28978 Section des sciences pharmaceutiques (FARMA) author Tille Jean-Christophe Division of Clinical Pathology, Geneva University Hospitals, Geneva, Switzerland 87627 author Voegel Clarissa D. 0000-0002-5480-7956 Department of Nephrology and Hypertension, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland author Nowak-Sliwinska Patrycja 0000-0002-8299-0444 School of Pharmaceutical Sciences, University of Geneva, Geneva, Switzerland 848409 Section des sciences pharmaceutiques (FARMA) author Bourquin Carole 0000-0003-3862-4583 School of Pharmaceutical Sciences, University of Geneva, Geneva, Switzerland 854541 Section des sciences pharmaceutiques (FARMA) author Pommier Aurélien 0009-0001-6540-1863 School of Pharmaceutical Sciences, University of Geneva, Geneva, Switzerland 885291 2286820 10.1080/2162402X.2023.2286820 38170044 2162-4011 PMC10761155 https://www.tandfonline.com/doi/full/10.1080/2162402X.2023.2286820 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 immunohisto- chemistry 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. Glucocorticoids HSD11B1 Immunotherapy Renal cancer Steroidogenesis Dewey 616.0757 Dewey 615 Dewey 616 Dewey 617 31 Section des sciences pharmaceutiques 17 56 Département de médecine 221 62 Département de radiologie et informatique médicale 227 63 Département d'anesthésiologie, pharmacologie, soins intensifs et urgences 229 false 881 Sciences analytiques 1278 Immunopharmacologie du cancer 1388 Cancers de la femme 1040 1222 Laboratoire de neuroimagerie et de traceurs moléculaires innovants 984 523 CIBM 863 Oncoimmunology 13 1 4f1a466a-e57e-4337-9319-bf902423a1bb Article (Published version) Public Activation of endogenous glucocorti.pdf 4313228 application/pdf CC BY-4.0 32f4c4c8d8e1cfdf71eba749ff4d4917c9592ed5e01557e8289dea71e0660081 openAccess Faculté des sciences / Section des sciences pharmaceutiques Faculté de médecine / Section de médecine clinique / Département de médecine Faculté de médecine / Section de médecine clinique / Département de radiologie et informatique médicale Faculté de médecine / Section de médecine clinique / Département d'anesthésiologie, pharmacologie, soins intensifs et urgences

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