Skin Cancer Unit of the Dermatology Department, Medical Faculty, West German Cancer Center, University Duisburg-Essen, Essen, Germany.
German Cancer Consortium (DKTK), Partner Site Essen/Düsseldorf, Essen, Germany.
J Immunother Cancer. 2023 Apr 7;11(4):e004150. doi: 10.1136/jitc-2021-004150.
Immune 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.
We 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.
Here, 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).
As 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.
肿瘤的免疫反应受到负反馈调节。阻断 T 细胞表达的程序性细胞死亡蛋白 1（PD-1）或其配体 PD-L1 的免疫检查点抑制剂（ICIs）显著改善了癌症的治疗效果，尤其是恶性黑色素瘤。然而，反应和持久性是可变的，这表明存在额外的关键负反馈机制，需要针对这些机制来提高治疗效果。
我们使用了不同的同源黑色素瘤小鼠模型，并进行了 PD-1 阻断，以确定新的负免疫调节机制。我们在黑色素瘤模型中使用了基因功能获得和缺失方法以及小分子抑制剂应用来验证靶点。我们通过 RNA-seq、免疫荧光和流式细胞术分析了经治疗和未经治疗的小鼠的黑色素瘤组织，以检测肿瘤微环境中通路活性和免疫细胞组成的变化。我们通过免疫组织化学分析了黑色素瘤患者的组织切片以及公开的单细胞 RNA-seq 数据，并将靶基因表达与 ICIs 的临床反应相关联。
在这里，我们发现 11-β-羟类固醇脱氢酶-1（HSD11B1）是一种在组织中将无活性糖皮质激素转化为有活性形式的酶，是 T 细胞免疫治疗的负反馈机制。糖皮质激素是免疫反应的强效抑制剂。HSD11B1 在黑色素瘤的不同细胞区室中表达，特别是髓样细胞，但也在 T 细胞和黑色素瘤细胞中表达。在小鼠黑色素瘤中强制表达 HSD11B1 会限制 PD-1 阻断的疗效，而小分子 HSD11B1 抑制剂则以 CD8 T 细胞依赖的方式改善反应。从机制上讲，HSD11B1 抑制与 PD-1 阻断联合增强了 T 细胞产生干扰素-γ。干扰素通路的激活与对黑色素瘤细胞的抗增殖作用相关联，这与对 PD-1 阻断的敏感性相关。此外，在通过不同方法（scRNA-seq、免疫组织化学）分析的两个独立的晚期黑色素瘤患者队列中，高水平的 HSD11B1（主要由肿瘤相关巨噬细胞表达）与对 ICI 治疗的反应不佳相关。
由于 HSD11B1 抑制剂是代谢疾病药物开发的重点，我们的数据表明了一种药物重新利用策略，即将 HSD11B1 抑制剂与 ICIs 联合使用，以改善黑色素瘤免疫治疗。此外，我们的工作还描绘了潜在的注意事项，强调了需要仔细进行患者分层。
