NDR1 通过 USP10 介导 PD-L1 去泛素化以促进前列腺癌免疫逃逸。

NDR1 mediates PD-L1 deubiquitination to promote prostate cancer immune escape via USP10.

机构信息

Department of Urology, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361101, China.

Department of Urology, Changhai Hospital, Naval Medical University (Second Military Medical University), Shanghai, China.

出版信息

Cell Commun Signal. 2024 Sep 3;22(1):429. doi: 10.1186/s12964-024-01805-5.

DOI:10.1186/s12964-024-01805-5

PMID:39227807

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11370014/

Abstract

Prostate cancer (PCa) is one of the most common male genitourinary system malignancies. Despite the significant benefits of anti-PD-L1 immune checkpoint inhibitor therapy in other cancers, the reasons for its poor therapeutic efficacy in prostate cancer (PCa) remain unclear.NDR1 plays an important role in innate immunity, but its role in tumor immunity and immunotherapy has not been investigated. The role of NDR1 in the immune microenvironment of PCa and the related mechanisms are unknown. Here, we found a positive correlation between NDR1 and PD-L1 expression in PCa. NDR1 significantly inhibits CD8 + T cell infiltration and function, thereby promoting immune escape in prostate cancer.More importantly, NDR1 inhibition significantly enhanced CD8 + T cell activation, which enhanced the therapeutic effect of anti-PD-L1. Mechanistic studies revealed that NDR1 inhibits ubiquitination-mediated PD-L1 degradation via the deubiquitinase USP10, upregulates PD-L1, and promotes PCa immune escape. Thus, our study suggests a unique PD-L1 regulatory mechanism underlying PCa immunotherapy failure. The significance of NDR1 in PCa immune escape and its mechanism of action were clarified, and combined NDR1/PD-L1 inhibition was suggested as an approach to boost PCa immunotherapy effectiveness.

摘要

前列腺癌 (PCa) 是男性泌尿生殖系统最常见的恶性肿瘤之一。尽管抗 PD-L1 免疫检查点抑制剂治疗在其他癌症中具有显著疗效，但其在前列腺癌 (PCa) 中疗效不佳的原因仍不清楚。NDR1 在先天免疫中发挥重要作用，但它在肿瘤免疫和免疫治疗中的作用尚未得到研究。NDR1 在 PCa 免疫微环境中的作用及其相关机制尚不清楚。在这里，我们发现 NDR1 与 PCa 中 PD-L1 的表达呈正相关。NDR1 显著抑制 CD8+T 细胞浸润和功能，从而促进前列腺癌的免疫逃逸。更重要的是，NDR1 抑制显著增强了 CD8+T 细胞的激活，从而增强了抗 PD-L1 的治疗效果。机制研究表明，NDR1 通过去泛素酶 USP10 抑制泛素化介导的 PD-L1 降解，上调 PD-L1，并促进 PCa 免疫逃逸。因此，我们的研究提示了一种独特的 PD-L1 调节机制，该机制可能是导致 PCa 免疫治疗失败的原因。阐明了 NDR1 在 PCa 免疫逃逸中的意义及其作用机制，并提出了联合 NDR1/PD-L1 抑制作为增强 PCa 免疫治疗效果的一种方法。