OTUD1 downregulates PD-L1 expression by deubiquitinating STAT3 and promotes the immune response in CcRCC.

IF 6.6 2区医学 Q1 Medicine

Cellular Oncology Pub Date : 2025-06-12 DOI:10.1007/s13402-025-01079-0

Huaiyuan Liang, Xinlin Liu, Wanyang Guo, Wei Xiong, Da Ren, Wentao Liu

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引用次数: 0

Abstract

Background: Clear cell renal cell carcinoma (ccRCC) is the most common malignant tumor of the urinary system and has the highest mortality rate. In addition to surgical tumor reduction, systemic drug therapy is the most important treatment method for metastatic renal cancer. In recent years, immunotherapeutic drugs represented by PD-1 antibodies have been used in the treatment of metastatic ccRCC and achieved good therapeutic effects. However, due to the occurrence of immune escape, only about 50-60% of patients with advanced renal cancer can significantly benefit from immunotherapy. The mechanism of immune escape is extremely complex and has not been clarified. We intend to delve into the driving mechanisms of immune evasion in ccRCC and explore potential targets for intervention.

Methods: In this study, we analyzed the expression of OTUD1 and related pathways in ccRCC through TCGA, GEO dataset, and cBioPortal web tool. At the same time, a mouse model of allogeneic transplanted clear cell renal cell carcinoma was constructed, and the effect of OTUD1 on anti-PD1 antibody therapy was discussed. Experiments such as co-IP, flow cytometry, and RNA-seq analysis were used to investigate the mechanism by which OTUD1 regulates immunity through STAT3.

Results: This study reveals that OTUD1 suppresses PD-L1 expression and enhances antitumor immunity in clear cell renal cell carcinoma (ccRCC) by deubiquitinating and stabilizing STAT3, thereby inhibiting its nuclear translocation and transcriptional activity. As a key regulator of the JAK-STAT pathway, OTUD1 disrupts PD-1/PD-L1-mediated immune evasion, offering a potential therapeutic strategy to improve immunotherapy responses in ccRCC. These findings highlight the OTUD1-STAT3-PD-L1 axis as a novel mechanism for overcoming immune checkpoint resistance.

Conclusion: Overall, we demonstrate that OTUD1 interacts with STAT3 and deubiquitinates, inhibits its nuclear translocation and activity, and ultimately inhibits immune evasion of ccRCC by downregulating PD-L1.

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OTUD1通过去泛素化STAT3下调PD-L1表达，促进CcRCC的免疫应答。

背景：透明细胞肾细胞癌（ccRCC）是泌尿系统最常见的恶性肿瘤，死亡率最高。除手术减瘤外，全身药物治疗是转移性肾癌最重要的治疗方法。近年来，以PD-1抗体为代表的免疫治疗药物已被用于转移性ccRCC的治疗，并取得了良好的治疗效果。然而，由于免疫逃逸的发生，只有约50-60%的晚期肾癌患者能从免疫治疗中明显获益。免疫逃逸的机制极其复杂，目前尚未明确。我们打算深入研究ccRCC中免疫逃避的驱动机制，并探索潜在的干预靶点。方法：本研究通过TCGA、GEO数据集和cBioPortal网络工具分析OTUD1及其相关通路在ccRCC中的表达。同时构建小鼠同种异体移植透明细胞肾细胞癌模型，探讨OTUD1对抗pd1抗体治疗的作用。通过co-IP、流式细胞术、RNA-seq分析等实验，探讨OTUD1通过STAT3调控免疫的机制。结果：本研究发现OTUD1通过去泛素化和稳定STAT3，抑制透明细胞肾细胞癌（clear cell renal cell carcinoma, ccRCC）中PD-L1的表达，增强抗肿瘤免疫，从而抑制STAT3的核易位和转录活性。作为JAK-STAT通路的关键调节因子，OTUD1破坏PD-1/ pd - l1介导的免疫逃避，为改善ccRCC的免疫治疗反应提供了一种潜在的治疗策略。这些发现突出了OTUD1-STAT3-PD-L1轴作为克服免疫检查点抵抗的新机制。结论：总的来说，我们证明OTUD1与STAT3和去泛素化相互作用，抑制其核易位和活性，最终通过下调PD-L1抑制ccRCC的免疫逃避。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cellular Oncology Biochemistry, Genetics and Molecular Biology-Cancer Research

CiteScore

10.40

自引率

1.50%

发文量

审稿时长

16 weeks

期刊介绍： The Official Journal of the International Society for Cellular Oncology Focuses on translational research Addresses the conversion of cell biology to clinical applications Cellular Oncology publishes scientific contributions from various biomedical and clinical disciplines involved in basic and translational cancer research on the cell and tissue level, technical and bioinformatics developments in this area, and clinical applications. This includes a variety of fields like genome technology, micro-arrays and other high-throughput techniques, genomic instability, SNP, DNA methylation, signaling pathways, DNA organization, (sub)microscopic imaging, proteomics, bioinformatics, functional effects of genomics, drug design and development, molecular diagnostics and targeted cancer therapies, genotype-phenotype interactions. A major goal is to translate the latest developments in these fields from the research laboratory into routine patient management. To this end Cellular Oncology forms a platform of scientific information exchange between molecular biologists and geneticists, technical developers, pathologists, (medical) oncologists and other clinicians involved in the management of cancer patients. In vitro studies are preferentially supported by validations in tumor tissue with clinicopathological associations.