Cancer is the second cause of death worldwide and renal cancer is the tenth most common cancer in developed countries. Even though patients with renal cancer usually respond to immune checkpoint inhibitors (ICI) which aim to restore the antitumor immune response in patients, resistance mechanisms occur and the 5-year survival rate in USA is only 12% of patients with metastatic disease. Therefore, novel treatments are required to overcome resistance mechanisms to current immunotherapies in renal cancer. One of the potential resistance mechanisms is the alteration of tumor and immune cell metabolism, which results in a reduction of antitumor immunity. Neo-steroidogenesis occurs in tumor and endogenous steroids have strong immunomodulatory functions, but their role in resistance to immunotherapy in cancer is poorly understood. In this thesis, we explored the potential of inhibiting the endogenous glucocorticoid pathway to improve the antitumor immune response and the efficacy of ICI in renal cancer.
Using bioinformatic analysis of TCGA data, we found that the glucocorticoid pathway was strongly associated with clinical outcome of renal cancer patients. HSD11B1 regenerates inactive glucocorticoids into active glucocorticoids and is the main peripheral glucocorticoid producer. Interestingly, HSD11B1 expression was associated with a poor clinical outcome and correlated with immunosuppressive gene expression in renal cancer patients. We also found that it was mainly expressed in immune infiltrated cells in human renal cancer samples.
Having observed that HSD11B1 expression was associated with immune components, we investigated the impact of HSD11B1 activity in immune cells. In murine and human in vitro assays, we demonstrated that HSD11B1 inhibition increases the T cell dependent killing of tumor cells by stimulating the antigen-mediated T cell activation, and treatment with an HSD11B1 inhibitor synergized with anti-PD-1 to improve the efficacy of ICI. Therefore, with the stated goal of repurposing HSD11B1 inhibitor in cancer treatment, several inhibitors were tested and a patent was filed to protect the use of HSD11B1 inhibitor in combination with ICI.
As immune activation was improved by HSD11B1 inhibition in vitro, we investigated the effect of the glucocorticoid pathway inhibition on the antitumor immune response in vivo. HSD11B1 inhibition in combination with ICI or resiquimod demonstrated an improvement of the efficacy of immunotherapy in s.c. and intra-renal mouse cancer models. Combination with mifepristone, a glucocorticoid receptor inhibitor, and anti-PD-1 showed a better outcome in subcutaneous renal mouse cancer than monotherapy, with an enhancement of immune related pathways and collagen metabolism in the tumor. However, further studies need to be carried out to understand the underlying mechanisms involved in this antitumor immune response, especially the role of the collagen metabolism and its impact on immune cell activity.
To conclude, this thesis supports the hypothesis that the use of HSD11B1 inhibitor and more generally, inhibition of the glucocorticoid pathway, in combination with immunotherapy could be beneficial in some renal cancer patients. These findings highlight the role of endogenous glucocorticoids on the antitumor immune response and pave the way for new treatment combinations in renal cancer, especially for patients exhibiting resistance to ICI.
