Eloise Dupuychaffray

High mobility group box protein 1 (HMGB1) is a ubiquitous protein that has multiple functions in the nucleus and cytosol. Following release into the extracellular space, HMGB1 acts as a mediator of inflammation. HMGB1 is overexpressed in many cancers and has both oncogenic and antitumoral effects. Here we investigated the role of HMGB1 expression by cancer cells in the antitumor immune response. Subcutaneous tumors were induced in mice by injection of wild-type or HMGB1-low engineered syngeneic cancer cells. Tumor growth and immune infiltration were assessed, and gene expression was analysed in whole tumors and isolated tumor cells by RNA sequencing analysis. Downregulation of cancer cell-intrinsic HMGB1 prevented tumor growth and reprogrammed the tumor microenvironment into a more inflamed phenotype. Tumor growth was not impacted in immunodeficient mice or in mice deficient in CD8 ⁺ T cells, demonstrating that the impact of HMGB1 downregulation on tumor progression was immune-dependent and mediated by CD8 ⁺ T cells. Transcriptional profiling showed that HMGB1 ^low tumors were enriched in immune pathways such as antigen presentation, T-cell receptor and cytokine signalling. Immune activation was robust and detectable in both tumor tissue and secondary lymphoid organs of mice bearing HMGB1 ^low tumors, but this did not facilitate immune infiltration of wild-type tumors that had been co-injected in the contralateral flank. We propose that tumor cell-intrinsic HMGB1 plays a critical role in modulating the local tumor microenvironment and in limiting anticancer immune responses. Thus, targeting cancer cell-intrinsic HMGB1 may represent a novel approach to improve the outcome of cancer immunotherapy.

Obesity increases cancer risk, yet obese patients often respond better to cancer immunotherapy. In our study, we uncovered why: high estrogen levels, especially in obese men, boost the immune response triggered by immunotherapy. This reveals a key role for estrogens in improving treatment effectiveness.

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.