SUMOylation inhibitors activate anti-tumor immunity by reshaping the immune microenvironment in a preclinical model of hepatocellular carcinoma.

IF 4.9 2区 医学 Q2 CELL BIOLOGY
Cellular Oncology Pub Date : 2024-04-01 Epub Date: 2023-12-06 DOI:10.1007/s13402-023-00880-z
Zengbin Wang, Banglun Pan, Lili Su, Huahui Yu, Xiaoxuan Wu, Yuxin Yao, Xiaoxia Zhang, Jiacheng Qiu, Nanhong Tang
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引用次数: 0

Abstract

Purpose: High levels of heterogeneity and immunosuppression characterize the HCC immune microenvironment (TME). Unfortunately, the majority of hepatocellular carcinoma (HCC) patients do not benefit from immune checkpoint inhibitors (ICIs) therapy. New small molecule therapies for the treatment of HCC are the goal of our research.

Methods: SUMOylation inhibitors (TAK-981 and ML-792) were evaluated for the treatment of preclinical mouse HCC models (including subcutaneous and orthotopic HCC models). We profile immune cell subsets from tumor samples after SUMOylation inhibitors treatment using single-cell RNA sequencing (scRNA-seq), mass cytometry (CyTOF), flow cytometry, and multiple immunofluorescences (mIF).

Results: We discover that SUMOylation is higher in HCC patient samples compared to normal liver tissue. TAK-981 and ML-792 decrease SUMOylation at nanomolar levels in HCC cells and also successfully reduced the tumor burden. Analysis combining scRNA-seq and CyTOF demonstrate that treatment with SUMOylation inhibitors reduces the exhausted CD8+T (Tex) cells while enhancing the cytotoxic NK cells, M1 macrophages and cytotoxic T lymphocytes (CTL) in preclinical mouse HCC model. Furthermore, SUMOylation inhibitors have the potential to activate innate immune signals from CD8+T, NK and macrophages while promoting TNFα and IL-17 secretion. Most notably, SUMOylation inhibitors can directly alter the TME by adjusting the abundance of intestinal microbiota, thereby restoring anti-tumor immunity in HCC models.

Conclusions: This preclinical study suggests that SUMO signaling inhibitors may be beneficial for the treatment of HCC.

Abstract Image

在肝细胞癌临床前模型中,SUMOylation 抑制剂通过重塑免疫微环境来激活抗肿瘤免疫。
目的:高度异质性和免疫抑制是肝癌免疫微环境(TME)的特点。不幸的是,大多数肝细胞癌(HCC)患者并不能从免疫检查点抑制剂(ICIs)治疗中获益。治疗 HCC 的新型小分子疗法是我们的研究目标:方法:我们评估了 SUMOylation 抑制剂(TAK-981 和 ML-792)用于治疗临床前小鼠 HCC 模型(包括皮下和正位 HCC 模型)。我们使用单细胞 RNA 测序(scRNA-seq)、质控细胞仪(CyTOF)、流式细胞仪和多重免疫荧光(mIF)分析了 SUMOylation 抑制剂治疗后肿瘤样本中的免疫细胞亚群:结果:我们发现,与正常肝组织相比,HCC 患者样本中的 SUMO 化程度更高。TAK-981和ML-792能在纳摩尔水平上降低HCC细胞中的SUMOylation,并成功减轻肿瘤负担。结合 scRNA-seq 和 CyTOF 的分析表明,在临床前小鼠 HCC 模型中,使用 SUMOylation 抑制剂可减少耗竭的 CD8+T (Tex)细胞,同时增强细胞毒性 NK 细胞、M1 巨噬细胞和细胞毒性 T 淋巴细胞(CTL)。此外,SUMOylation 抑制剂还有可能激活来自 CD8+T、NK 和巨噬细胞的先天性免疫信号,同时促进 TNFα 和 IL-17 的分泌。最值得注意的是,SUMOylation 抑制剂可以通过调整肠道微生物群的丰度直接改变 TME,从而恢复 HCC 模型的抗肿瘤免疫:这项临床前研究表明,SUMO 信号抑制剂可能有益于治疗 HCC。
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
Cellular Oncology ONCOLOGY-CELL BIOLOGY
CiteScore
10.30
自引率
1.50%
发文量
86
审稿时长
12 months
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.
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