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.

Title	Published in	Year	Views	Downloads

Activation of endogenous glucocorticoids by HSD11B1 inhibits the antitumor immune response in renal cancer	Oncoimmunology	2023	132	21
Harnessing the immune system to fight cancer with Toll-like receptor and RIG-I-like receptor agonists	Pharmacological Research	2019	444	748

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Pommier, Aurélien