组蛋白去泛素化酶Bap1的缺失会引发抗肿瘤免疫。

IF 6.6 2区 医学 Q1 Medicine Cellular Oncology Pub Date : 2024-08-14 DOI:10.1007/s13402-024-00978-y
Hong Chang, Mingxia Li, Linlin Zhang, Meng Li, Swee Hoe Ong, Zhiwei Zhang, Jie Zheng, Xiang Xu, Yu Zhang, Jing Wang, Xingjie Liu, Kairui Li, Yao Luo, Haiyun Wang, Zhichao Miao, Xi Chen, Jie Zha, Yong Yu
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摘要

目的:使用 PD-L1 阻断剂的免疫疗法仅对一小部分癌症患者有效,而且耐药性很常见。这就强调了了解癌症免疫逃避和抗药性机制的重要性:基因组规模的CRISPR-Cas9筛选发现Bap1是PD-L1表达的调控因子。为了测量肿瘤大小和存活率,将肿瘤细胞皮下注射到合成WT小鼠和免疫缺陷小鼠体内。使用流式细胞术、RNA-seq和CUT&Tag-seq分析方法检测了Bap1缺失肿瘤的表型和转录特征:结果:我们发现,癌细胞中组蛋白去泛素化酶Bap1的缺失会激活依赖于cDC1-CD8+ T细胞的抗肿瘤免疫。Bap1 的缺失导致与抗肿瘤免疫反应相关的基因增加,而与免疫逃避相关的基因减少。结果,肿瘤微环境变得炎症,cDC1细胞和效应CD8+ T细胞增多,但中性粒细胞和调节性T细胞减少。我们还发现,Bap1缺失肿瘤的消除取决于肿瘤MHCI分子和Fas介导的CD8+ T细胞细胞毒性。我们对TCGA数据的分析进一步支持了这些发现,显示在各种人类癌症中,BAP1表达与活化的DC和T细胞细胞毒性的mRNA特征之间存在反向相关性:组蛋白去泛素化酶BAP1可作为肿瘤分层的生物标记物,也可作为癌症免疫疗法的潜在治疗靶点。
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Loss of histone deubiquitinase Bap1 triggers anti-tumor immunity.

Purpose: Immunotherapy using PD-L1 blockade is effective in only a small group of cancer patients, and resistance is common. This emphasizes the importance of understanding the mechanisms of cancer immune evasion and resistance.

Methods: A genome-scale CRISPR-Cas9 screen identified Bap1 as a regulator of PD-L1 expression. To measure tumor size and survival, tumor cells were subcutaneously injected into both syngeneic WT mice and immunocompromised mice. The phenotypic and transcriptional characteristics of Bap1-deleted tumors were examined using flow cytometry, RNA-seq, and CUT&Tag-seq analysis.

Results: We found that loss of histone deubiquitinase Bap1 in cancer cells activates a cDC1-CD8+ T cell-dependent anti-tumor immunity. The absence of Bap1 leads to an increase in genes associated with anti-tumor immune response and a decrease in genes related to immune evasion. As a result, the tumor microenvironment becomes inflamed, with more cDC1 cells and effector CD8+ T cells, but fewer neutrophils and regulatory T cells. We also found that the elimination of Bap1-deleted tumors depends on the tumor MHCI molecule and Fas-mediated CD8+ T cell cytotoxicity. Our analysis of TCGA data further supports these findings, showing a reverse correlation between BAP1 expression and mRNA signatures of activated DCs and T-cell cytotoxicity in various human cancers.

Conclusion: The histone deubiquitinase Bap1 could be used as a biomarker for tumor stratification and as a potential therapeutic target for cancer immunotherapies.

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来源期刊
Cellular Oncology
Cellular Oncology Biochemistry, Genetics and Molecular Biology-Cancer Research
CiteScore
10.40
自引率
1.50%
发文量
0
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.
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