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

作　　者：Fenglian He Zhongen Wu Chenglong Liu Yuanyuan Zhu Yan Zhou Enming Tian Rina Rosin-Arbesfeld Dehua Yang Ming-Wei Wang Di Zhu 

机构地区：[1]Department of Pharmacology,Minhang Hospital,and Key Laboratory of Smart Drug Delivery,Shanghai Engineering Research Center of Immune Therapy,School of Pharmacy,Fudan University,Shanghai 201203,China [2]The National Center for Drug Screening and the CAS Key Laboratory of Receptor Research,Shanghai Institute of Materia Medica,Chinese Academy of Sciences(CAS),Shanghai 201203,China [3]Department of Microbiology and Immunology,Sackler Faculty of Medicine,Tel Aviv University,Tel Aviv,Israel [4]Department of Pharmacology,School of Basic Medical Sciences,Fudan University,Shanghai 200032,China [5]Research Center for Deepsea Bioresources,Sanya,China [6]Department of Chemistry,School of Science,The University of Tokyo,Tokyo,Japan [7]Engineering Research Center of Tropical Medicine Innovation and Transformation of Ministry of Education,School of Pharmacy,Hainan Medical University,Haikou,China [8]Shandong Academy of Pharmaceutical Science,Jinan,China

出　　处：《Signal Transduction and Targeted Therapy》2024年第6期2804-2818,共15页信号转导与靶向治疗（英文）

基　　金：the National Natural Science Foundation of China with grants 81872895 and 82073881 awarded to D.Z.,and 81872915,82073904,and 82011530150 to M.-W.W.;the Shanghai Municipal Education Commission under the Shanghai Top-Level University Capacity Building Program(DGF817029-04 to M.-W.W.);the Shanghai Science and Technology Commission with grants 18ZR1403900,20430713600,and 18JC1413800 to D.Z;Innovative Drug and Evaluation Innovation Team for Tumor Immunotherapy of Jinan Science and Technology Bureau(No.2020GXRC041 to D.Z.);funded by the Fudan School of Pharmacy and Minhang Hospital Joint Research Fund(RO-MY201712 to D.Z.);the Fudan-SIMM Joint Research Fund(FU-SIMM20181010 to D.Z.and D.Y.).

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-κB/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.

关 键 词：IMMUNITY TARGETING markedly 

分 类 号：R730.51[医药卫生—肿瘤]