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.

Cytokines are immune modulators which can enhance the immune response and have been proven to be an effective class of immunotherapy. Nevertheless, the clinical use of cytokines in cancer treatment has faced several challenges associated with poor pharmacokinetic properties and the occurrence of adverse effects. Immunocytokines (ICKs) have emerged as a promising approach to overcome the pharmacological limitations observed with cytokines. ICKs are fusion proteins designed to deliver cytokines in the tumor microenvironment by taking advantage of the stability and specificity of immunoglobulin-based scaffolds. Several technological approaches have been developed. This review focuses on ICKs designed with the most impactful cytokines in the cancer field: IL-2, TNFα, IL-10, IL-12, IL-15, IL-21, IFNγ, GM-CSF, and IFNα. An overview of the pharmacological effects of the naked cytokines and ICKs tested for cancer therapy is detailed. A particular emphasis is given on the immunomodulatory effects of ICKs associated with their technological design. In conclusion, this review highlights active ways of development of ICKs. Their already promising results observed in clinical trials are likely to be improved with the advances in targeting technologies such as cytokine/linker engineering and the design of multispecific antibodies with tumor targeting and immunostimulatory functional properties.

Although obesity is a major risk factor for cancer, it may also improve the response to cancer therapy. Here we investigated the impact of obesity on the efficacy of immune checkpoint inhibitors (ICI). In male mice, obesity promoted tumor growth but enhanced the response to ICI. This was associated with higher expression of immune-related genes within the tumor and enhanced infiltration of tumor-specific CD8 ⁺ T cells. Further, obesity in mice was associated with higher estrogen levels and enrichment of estrogen response genes in the tumor, and anti–programmed cell death 1 (anti–PD-1) efficacy was reduced upon administration of the aromatase inhibitor letrozole, which blocks the production of estrogens. Mechanistically, adipocyte-derived estrogens increased antigen presentation by dendritic cells and tumor-specific CD8 ⁺ T cell cytotoxicity. Last, overweight and obese men with melanoma responded better to ICI, with high estrogen levels being associated with improved response and survival. Our results suggest that estrogens may serve as a predictive factor of response to ICI in men with melanoma.

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.