Chang Hong, Li Mingxia, Zhang Linlin, Li Meng, Ong Swee Hoe, Zhang Zhiwei, Zheng Jie, Xu Xiang, Zhang Yu, Wang Jing, Liu Xingjie, Li Kairui, Luo Yao, Wang Haiyun, Miao Zhichao, Chen Xi, Zha Jie, Yu Yong
Department of Hematology, Tongji Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, 1239 Siping Road, Shanghai, 200092, China.
Wellcome Sanger Institute, Hinxton, Cambridge, CB10 1HH, UK.
Cell Oncol (Dordr). 2025 Feb;48(1):183-203. doi: 10.1007/s13402-024-00978-y. Epub 2024 Aug 14.
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.
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.
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.
The histone deubiquitinase Bap1 could be used as a biomarker for tumor stratification and as a potential therapeutic target for cancer immunotherapies.
使用程序性死亡配体1（PD-L1）阻断的免疫疗法仅对一小部分癌症患者有效，且耐药现象普遍。这凸显了理解癌症免疫逃逸和耐药机制的重要性。
一项全基因组规模的CRISPR-Cas9筛选确定Bap1为PD-L1表达的调节因子。为了测量肿瘤大小和生存期，将肿瘤细胞皮下注射到同基因野生型小鼠和免疫缺陷小鼠体内。使用流式细胞术、RNA测序和切割与标签测序分析来检测缺失Bap1的肿瘤的表型和转录特征。
我们发现癌细胞中组蛋白去泛素化酶Bap1的缺失激活了一种依赖于浆细胞样树突状细胞1（cDC1）-细胞毒性T淋巴细胞（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，与免疫逃逸相关的基因减少。结果，肿瘤微环境变得炎症化，有更多的cDC1细胞和效应CD8 T细胞，但中性粒细胞和调节性T细胞较少。我们还发现，清除缺失Bap1的肿瘤依赖于肿瘤主要组织相容性复合体I类（MHCI）分子和Fas介导的CD8 T细胞细胞毒性。我们对癌症基因组图谱（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表达与活化树突状细胞和T细胞细胞毒性的mRNA特征呈负相关。
组蛋白去泛素化酶Bap1可作为肿瘤分层的生物标志物以及癌症免疫疗法的潜在治疗靶点。
