Glucocorticoid activation by HSD11B1 limits T cell-driven interferon signaling and response to PD-1 blockade in melanoma

Abstract

BackgroundImmune responses against tumors are subject to negative feedback regulation. Immune checkpoint inhibitors (ICIs) blocking Programmed cell death protein 1 (PD-1), a receptor expressed on T cells, or its ligand PD-L1 have significantly improved the treatment of cancer, in particular malignant melanoma. Nevertheless, responses and durability are variables, suggesting that additional critical negative feedback mechanisms exist and need to be targeted to improve therapeutic efficacy.MethodsWe used different syngeneic melanoma mouse models and performed PD-1 blockade to identify novel mechanisms of negative immune regulation. Genetic gain-of-function and loss-of-function approaches as well as small molecule inhibitor applications were used for target validation in our melanoma models. We analyzed mouse melanoma tissues from treated and untreated mice by RNA-seq, immunofluorescence and flow cytometry to detect changes in pathway activities and immune cell composition of the tumor microenvironment. We analyzed tissue sections of patients with melanoma by immunohistochemistry as well as publicly available single-cell RNA-seq data and correlated target expression with clinical responses to ICIs.ResultsHere, we identified 11-beta-hydroxysteroid dehydrogenase-1 (HSD11B1), an enzyme that converts inert glucocorticoids into active forms in tissues, as negative feedback mechanism in response to T cell immunotherapies. Glucocorticoids are potent suppressors of immune responses. HSD11B1 was expressed in different cellular compartments of melanomas, most notably myeloid cells but also T cells and melanoma cells. Enforced expression of HSD11B1 in mouse melanomas limited the efficacy of PD-1 blockade, whereas small molecule HSD11B1 inhibitors improved responses in a CD8+T cell-dependent manner. Mechanistically, HSD11B1 inhibition in combination with PD-1 blockade augmented the production of interferon-γ by T cells. Interferon pathway activation correlated with sensitivity to PD-1 blockade linked to anti-proliferative effects on melanoma cells. Furthermore, high levels of HSD11B1, predominantly expressed by tumor-associated macrophages, were associated with poor responses to ICI therapy in two independent cohorts of patients with advanced melanomas analyzed by different methods (scRNA-seq, immunohistochemistry).ConclusionAs HSD11B1 inhibitors are in the focus of drug development for metabolic diseases, our data suggest a drug repurposing strategy combining HSD11B1 inhibitors with ICIs to improve melanoma immunotherapy. Furthermore, our work also delineated potential caveats emphasizing the need for careful patient stratification.

Unlocking the potential of T‐cell metabolism reprogramming: Advancing single‐cell approaches for precision immunotherapy in tumour immunity

“…Several single‐cell studies have indicated that ILTC metabolism tends to shift towards FAO, which inhibits the release of the inflammatory regulator IL‐22, an initiating factor that increases the development of colitis following anti‐PD‐1 therapy 236 . Unexpectedly, combining metabolic modulators with ICI treatment may increase the incidence of irAEs 176 . This outcome underscores the need for rational solutions to overcome irAEs caused by ICIs by blocking the abnormal metabolic reprogramming of T cells or actively directing the T‐cell metabolic process.…”

“…236 Unexpectedly, combining metabolic modulators with ICI treatment may increase the incidence of irAEs. 176 This outcome underscores the need for rational solutions to overcome irAEs caused by ICIs by blocking the abnormal metabolic reprogramming of T cells or actively directing the T-cell metabolic process. Modifying the intestinal microbial system and thus enhancing immunotherapy often relies on short-chain fatty acids to ensure tumour cell histone acetylation, which creates a favourable environment for beneficial microorganisms and the antitumour immune system.…”

“…11‐β‐Hydroxysteroid dehydrogenase‐1 (HSD11B1) converts intracellular inert glucocorticoids into active glucocorticoids, not systemic glucocorticoids. Pharmacological inhibition of HSD11B1 protects against immune surveillance and the tumour‐killing capability of TILs and increases IFN‐γ signalling to induce immune checkpoint inhibitor (ICI) responses but possibly exacerbate the risk of immune‐related adverse events (irAEs) 176 …”

“…Pharmacological inhibition of HSD11B1 protects against immune surveillance and the tumourkilling capability of TILs and increases IFN-γ signalling to induce immune checkpoint inhibitor (ICI) responses but possibly exacerbate the risk of immune-related adverse events (irAEs). 176 Exogenous supplementation of nutrients consumed during TIL competition exerts a positive effect by restoring initial immune effector function. SAM, for example, is a substrate of histone methylases in CD8+ T cells, establishing a connection between methionine metabolism and epistatic modification.…”

“…Pharmacological inhibition of HSD11B1 protects against immune surveillance and the tumour‐killing capability of TILs and increases IFN‐γ signalling to induce immune checkpoint inhibitor (ICI) responses but possibly exacerbate the risk of immune‐related adverse events (irAEs). 176 …”