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

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

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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.

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

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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

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

Department of Microbiology and Immunology,Sackler Faculty of Medicine,Tel Aviv University,Tel Aviv,Israel

Department of Pharmacology,School of Basic Medical Sciences,Fudan University,Shanghai 200032,China

Research Center for Deepsea Bioresources,Sanya,China

Department of Chemistry,School of Science,The University of Tokyo,Tokyo,Japan

Engineering Research Center of Tropical Medicine Innovation and Transformation of Ministry of Education,School of Pharmacy,Hainan Medical University,Haikou,China

Shandong Academy of Pharmaceutical Science,Jinan,China

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National Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaShanghai Municipal Education Commission under the Shanghai Top-Level University Capacity Building ProgramShanghai Science and Technology CommissionShanghai Science and Technology CommissionShanghai Science and Technology CommissionInnovative Drug and Evaluation Innovation Team for Tumor Immunotherapy of Jinan Science and Technology BureauFudan School of Pharmacy and Minhang Hospital Joint Research FundFudan-SIMM Joint Research Fund

8187289582073881818729158207390482011530150DGF817029-0418ZR14039002043071360018JC14138002020GXRC041RO-MY201712FU-SIMM20181010

2024

10.1038/s41392-024-01838-9

信号转导与靶向治疗(英文)

信号转导与靶向治疗(英文)

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ISSN：
年,卷(期)：2024.9(6)