Loss of histone deubiquitinase Bap1 triggers anti-tumor immunity

Chang, Hong1; Li, Mingxia1; Zhang, Linlin1; Li, Meng5; Ong, Swee Hoe5; Zhang, Zhiwei1; Zheng, Jie1; Xu, Xiang1; Zhang, Yu1; Wang, Jing1; Liu, Xingjie1; Li, Kairui1; Luo, Yao1; Wang, Haiyun1; Miao, Zhichao6,7; Chen, Xi8; Zha, Jie2,4; Yu, Yong1

2024-08-01

10.1007/s13402-024-00978-y

CELLULAR ONCOLOGY   影响因子和分区

2211-3428

2211-3436

PurposeImmunotherapy 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.MethodsA 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.ResultsWe 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.ConclusionThe histone deubiquitinase Bap1 could be used as a biomarker for tumor stratification and as a potential therapeutic target for cancer immunotherapies.

Bap1 Tumor microenvironment PD-L1 Anti-tumor immunity

SCI

英语

其他

Oncology ; Cell Biology ; Pathology

Oncology ; Cell Biology ; Pathology

WOS:001290688400003

SPRINGER

MOLECULAR BIOLOGY & GENETICS

Web of Science

1.Tongji Univ, Tongji Hosp, Frontier Sci Ctr Stem Cell Res, Sch Life Sci & Technol, 1239 Siping Rd, Shanghai 200092, Peoples R China
2.Xiamen Univ, Affiliated Hosp 1, Dept Hematol, Xiamen, Peoples R China
3.Xiamen Univ, Inst Hematol, Sch Med, Xiamen, Peoples R China
4.Key Lab Xiamen Diag & Treatment Hematol Malignancy, Xiamen, Peoples R China
5.Wellcome Sanger Inst, Cambridge CB10 1HH, England
6.Tongji Univ, Shanghai Peoples Hosp Affiliated 4, Translat Res Inst Brain & Brain Like Intelligence, Sch Med, Shanghai 200081, Peoples R China
7.Guangzhou Med Univ, GIBH Joint Sch Life Sci, Guangdong Hong Kong Macau Joint Lab Cell Fate Regu, Guangzhou Lab, Hong Kong, Peoples R China
8.Southern Univ Sci & Technol, Dept Biol, 1088 Xueyuan Ave, Shenzhen 518055, Peoples R China

Chang, Hong,Li, Mingxia,Zhang, Linlin,et al. Loss of histone deubiquitinase Bap1 triggers anti-tumor immunity[J]. CELLULAR ONCOLOGY,2024.

Chang, Hong.,Li, Mingxia.,Zhang, Linlin.,Li, Meng.,Ong, Swee Hoe.,...&Yu, Yong.(2024).Loss of histone deubiquitinase Bap1 triggers anti-tumor immunity.CELLULAR ONCOLOGY.

Chang, Hong,et al."Loss of histone deubiquitinase Bap1 triggers anti-tumor immunity".CELLULAR ONCOLOGY (2024).