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

ABSTRACT

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.

KEYWORDS:

• Glucocorticoids
• HSD11B1
• immunotherapy
• renal cancer
• steroidogenesis

Acknowledgments

The authors thank Magdalena Rausch for support during the isolation of immune cells from RCC patients, Stéphane Germain for his help in the setting up of the orthotopic tumor model and Didier J. Colin who is head of the small animal preclinical imaging platform of Geneva.

Disclosure statement

No potential conflict of interest was reported by the authors.

Data availability statement

The data that support the findings of this study are available from the corresponding authors [CB, AP], upon reasonable request.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/2162402X.2023.2286820

Author contribution

AP, CB and HP designed and planned the study. HP, ED, GA, MA, JT, OE, JM, OB, EO, GV, CDV and AP performed the experiments and collected and analyzed the data. VGR, SR, JCT, and PNS contributed essential expertise and tools. AP, CB and HP wrote the paper. The paper was reviewed and approved by all authors.

Correction Statement

This article has been republished with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

This work was supported by Horizon 2020 UE No 641549 (SEFRI 15.0243), the Swiss National Science Foundation 310030_182317 and IZSTZ0_198887, the Swiss Cancer Research Foundation KFS 4535-08-2018-R, Innosuisse 44124.1 IP-LS, the Boninchi Foundation and the Schmidheiny Foundation.