Activation of endogenous glucocorticoids by HSD11B1 inhibits the antitumor immune response in renal cancer
SUMMARY
Although immune-based therapies have revolutionized the management of cancer, novel approaches are urgently needed to improve their outcome. The group of GCIR member Prof. Carole Bourquin, in this study led by Dr Aurélien Pommier, investigated the role of endogenous steroids in the resistance to cancer immunotherapy, as these have strong immunomodulatory functions. Using a publicly available database, they 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, they 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, they 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.
Full article: https://doi.org/10.1080/2162402X.2023.2286820
Funding: This work was supported by Horizon 2020 UE, the Swiss National Science Foundation, the Swiss Cancer Research Foundation, Innosuisse, the Boninchi Foundation and the Schmidheiny Foundation.
Why is it important?
Unprecedented advances have been made in the treatment of renal cancer through the use of immune checkpoint blockade, but some drivers of resistance are still unknown. This study highlights the regeneration of glucocorticoids pathway as a novel mechanism of resistance to immunotherapy. This work supports the hypothesis that the combination of an HSD11B1 inhibitor with immune checkpoint blockade may be beneficial in renal cancer patients.
