Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, Jiangsu Province, China.
School of Chemistry and Chemical Engineering, Southeast University, Nanjing, Jiangsu Province, China.
Nat Commun. 2022 Dec 12;13(1):7677. doi: 10.1038/s41467-022-35469-x.
Programmed death receptor-1 (PD-1) blockade have achieved some efficacy but only in a fraction of patients with hepatocellular carcinoma (HCC). Programmed cell death 1 ligand 1 (PD-L1) binds to its receptor PD1 on T cells to dampen antigen-tumor immune responses. However, the mechanisms underlying PD-L1 regulation are not fully elucidated. Herein, we identify that tumoral Prdm1 overexpression inhibits cell growth in immune-deficient mouse models. Further, tumoral Prdm1 overexpression upregulates PD-L1 levels, dampening anti-tumor immunity in vivo, and neutralizes the anti-tumor efficacy of Prdm1 overexpression in immune-competent mouse models. Mechanistically, PRDM1 enhances USP22 transcription, thus reducing SPI1 protein degradation through deubiquitination, which enhances PD-L1 transcription. Functionally, PD-1 mAb treatment reinforces the efficacy of Prdm1-overexpressing HCC immune-competent mouse models. Collectively, we demonstrate that the PRDM1-USP22-SPI1 axis regulates PD-L1 levels, resulting in infiltrated CD8 T cell exhaustion. Furthermore, PRDM1 overexpression combined with PD-(L)1 mAb treatment provides a therapeutic strategy for HCC treatment.
程序性死亡受体-1（PD-1）阻断在一定程度上具有疗效，但仅在部分肝细胞癌（HCC）患者中有效。程序性细胞死亡受体 1 配体 1（PD-L1）与 T 细胞上的受体 PD1 结合，以抑制抗原-肿瘤免疫反应。然而，PD-L1 调节的机制尚未完全阐明。在这里，我们发现肿瘤 Prdm1 过表达抑制免疫缺陷小鼠模型中的细胞生长。此外，肿瘤 Prdm1 过表达上调 PD-L1 水平，在体内抑制抗肿瘤免疫，并中和免疫功能正常的小鼠模型中 Prdm1 过表达的抗肿瘤疗效。从机制上讲，PRDM1 增强 USP22 的转录，从而通过去泛素化减少 SPI1 蛋白的降解，增强 PD-L1 的转录。从功能上讲，PD-1 mAb 治疗增强了 Prdm1 过表达的 HCC 免疫功能正常小鼠模型的疗效。总的来说，我们证明了 PRDM1-USP22-SPI1 轴调节 PD-L1 水平，导致浸润的 CD8 T 细胞耗竭。此外，PRDM1 过表达联合 PD-（L）1 mAb 治疗为 HCC 治疗提供了一种治疗策略。
