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Targeting BCL9/BCL9L enhances antigen presentation by promoting conventional type 1 dendritic cell (cDC1) activation and tumor infiltration

文献类型：期刊论文

作者He, Fenglian9,10; Wu, Zhongen9,10; Liu, Chenglong9,10; Zhu, Yuanyuan9,10; Zhou, Yan7,8; Tian, Enming9,10; Rosin-Arbesfeld, Rina6; Yang, Dehua7,8; Wang, Ming-Wei2,3,4,5; Zhu, Di1,5
刊名SIGNAL TRANSDUCTION AND TARGETED THERAPY
出版日期2024-05-29
卷号9期号:1页码:15
ISSN号2095-9907
DOI10.1038/s41392-024-01838-9
通讯作者Wang, Ming-Wei(mwwang@simm.ac.cn) ; Zhu, Di(zhudi@fudan.edu.cn)
英文摘要Conventional type 1 dendritic cells (cDC1) are the essential antigen-presenting DC subset in antitumor immunity. Suppressing B-cell lymphoma 9 and B-cell lymphoma 9-like (BCL9/BCL9L) inhibits tumor growth and boosts immune responses against cancer. However, whether oncogenic BCL9/BCL9L impairs antigen presentation in tumors is still not completely understood. Here, we show that targeting BCL9/BCL9L enhanced antigen presentation by stimulating cDC1 activation and infiltration into tumor. Pharmacological inhibition of BCL9/BCL9L with a novel inhibitor hsBCL9z96 or Bcl9/Bcl9l knockout mice markedly delayed tumor growth and promoted antitumor CD8+ T cell responses. Mechanistically, targeting BCL9/BCL9L promoted antigen presentation in tumors. This is due to the increase of cDC1 activation and tumor infiltration by the XCL1-XCR1 axis. Importantly, using single-cell transcriptomics analysis, we found that Bcl9/Bcl9l deficient cDC1 were superior to wild-type (WT) cDC1 at activation and antigen presentation via NF-kappa B/IRF1 signaling. Together, we demonstrate that targeting BCL9/BCL9L plays a crucial role in cDC1-modulated antigen presentation of tumor-derived antigens, as well as CD8+ T cell activation and tumor infiltration. Targeting BCL9/BCL9L to regulate cDC1 function and directly orchestrate a positive feedback loop necessary for optimal antitumor immunity could serve as a potential strategy to counter immune suppression and enhance cancer immunotherapy.
WOS关键词BRUTONS TYROSINE KINASE ; BETA-CATENIN ; MICROENVIRONMENT ; TAK1
资助项目National Natural Science Foundation of China (National Science Foundation of China)[81872895] ; National Natural Science Foundation of China (National Science Foundation of China)[82073881] ; National Natural Science Foundation of China (National Science Foundation of China)[81872915] ; National Natural Science Foundation of China (National Science Foundation of China)[82073904] ; National Natural Science Foundation of China (National Science Foundation of China)[82011530150] ; National Natural Science Foundation of China[DGF817029-04] ; Shanghai Municipal Education Commission under the Shanghai Top-Level University Capacity Building Program[18ZR1403900] ; Shanghai Municipal Education Commission under the Shanghai Top-Level University Capacity Building Program[20430713600] ; Shanghai Municipal Education Commission under the Shanghai Top-Level University Capacity Building Program[18JC1413800] ; Shanghai Science and Technology Commission[2020GXRC041] ; Innovative Drug and Evaluation Innovation Team for Tumor Immunotherapy of Jinan Science and Technology Bureau[RO-MY201712] ; Fudan School of Pharmacy and Minhang Hospital Joint Research Fund[FU-SIMM20181010] ; Fudan-SIMM Joint Research Fund
WOS研究方向Biochemistry & Molecular Biology ; Cell Biology
语种英语
WOS记录号WOS:001234816600002
出版者SPRINGERNATURE
源URL[http://119.78.100.183/handle/2S10ELR8/311812]  
专题中国科学院上海药物研究所
通讯作者Wang, Ming-Wei; Zhu, Di
作者单位1.Shandong Acad Pharmaceut Sci, Jinan, Peoples R China
2.Hainan Med Univ, Engn Res Ctr Trop Med Innovat & Transformat, Sch Pharm, Minist Educ, Haikou, Peoples R China
3.Univ Tokyo, Sch Sci, Dept Chem, Tokyo, Japan
4.Res Ctr Deepsea Bioresources, Sanya, Peoples R China
5.Fudan Univ, Sch Basic Med Sci, Dept Pharmacol, Shanghai 200032, Peoples R China
6.Tel Aviv Univ, Sackler Fac Med, Dept Microbiol & Immunol, Tel Aviv, Israel
7.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China
8.Chinese Acad Sci, Natl Ctr Drug Screening, Shanghai 201203, Peoples R China
9.Fudan Univ, Shanghai Engn Res Ctr Immune Therapy, Sch Pharm, Key Lab Smart Drug Delivery, Shanghai 201203, Peoples R China
10.Fudan Univ, Minhang Hosp, Sch Pharm, Dept Pharmacol, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 He, Fenglian,Wu, Zhongen,Liu, Chenglong,et al. Targeting BCL9/BCL9L enhances antigen presentation by promoting conventional type 1 dendritic cell (cDC1) activation and tumor infiltration[J]. SIGNAL TRANSDUCTION AND TARGETED THERAPY,2024,9(1):15.
APA He, Fenglian.,Wu, Zhongen.,Liu, Chenglong.,Zhu, Yuanyuan.,Zhou, Yan.,...&Zhu, Di.(2024).Targeting BCL9/BCL9L enhances antigen presentation by promoting conventional type 1 dendritic cell (cDC1) activation and tumor infiltration.SIGNAL TRANSDUCTION AND TARGETED THERAPY,9(1),15.
MLA He, Fenglian,et al."Targeting BCL9/BCL9L enhances antigen presentation by promoting conventional type 1 dendritic cell (cDC1) activation and tumor infiltration".SIGNAL TRANSDUCTION AND TARGETED THERAPY 9.1(2024):15.

入库方式： OAI收割

来源：上海药物研究所

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