Department of Radiation and Medical Oncology, Hubei Key Laboratory of Tumor Biological Behaviors, Hubei Cancer Clinical Study Center, Zhongnan Hospital of Wuhan University, 430071, Wuhan, China.
Frontier Science Center for Immunology and Metabolism, Medical Research Institute, School of Medicine, Wuhan University, 430071, Wuhan, China.
Nat Commun. 2022 Mar 31;13(1):1700. doi: 10.1038/s41467-022-29401-6.
Anti-PD-1/PD-L1 immunotherapy has achieved impressive therapeutic outcomes in patients with multiple cancer types. However, the underlined molecular mechanism(s) for moderate response rate (15-25%) or resistance to PD-1/PD-L1 blockade remains not completely understood. Here, we report that inhibiting the deubiquitinase, USP8, significantly enhances the efficacy of anti-PD-1/PD-L1 immunotherapy through reshaping an inflamed tumor microenvironment (TME). Mechanistically, USP8 inhibition increases PD-L1 protein abundance through elevating the TRAF6-mediated K63-linked ubiquitination of PD-L1 to antagonize K48-linked ubiquitination and degradation of PD-L1. In addition, USP8 inhibition also triggers innate immune response and MHC-I expression largely through activating the NF-κB signaling. Based on these mechanisms, USP8 inhibitor combination with PD-1/PD-L1 blockade significantly activates the infiltrated CD8 T cells to suppress tumor growth and improves the survival benefit in several murine tumor models. Thus, our study reveals a potential combined therapeutic strategy to utilize a USP8 inhibitor and PD-1/PD-L1 blockade for enhancing anti-tumor efficacy.
抗 PD-1/PD-L1 免疫疗法在多种癌症患者中取得了令人瞩目的治疗效果。然而，对于中等反应率（15-25%）或对 PD-1/PD-L1 阻断的耐药性的潜在分子机制尚不完全清楚。在这里，我们报告抑制去泛素化酶 USP8 通过重塑炎症性肿瘤微环境（TME），显著提高了抗 PD-1/PD-L1 免疫疗法的疗效。在机制上，USP8 抑制通过增加 TRAF6 介导的 PD-L1 的 K63 连接泛素化来增加 PD-L1 蛋白丰度，从而拮抗 PD-L1 的 K48 连接泛素化和降解。此外，USP8 抑制还通过激活 NF-κB 信号触发固有免疫反应和 MHC-I 表达。基于这些机制，USP8 抑制剂与 PD-1/PD-L1 阻断的联合应用可显著激活浸润的 CD8 T 细胞，抑制肿瘤生长，并提高几种小鼠肿瘤模型的生存获益。因此，我们的研究揭示了一种潜在的联合治疗策略，即利用 USP8 抑制剂和 PD-1/PD-L1 阻断来增强抗肿瘤疗效。
