By analyzing published gene expression datasets, He, Wu, Liu, and Zhu et al. showed that BCL9 expression is negatively associated with tumor antigen presentation, immune cell influx, and overall survival of patients with colon and breast cancers and melanoma. Using mouse cancer models, scRNAseq analyses showed that Bcl9/Bcl9l deletion or pharmacologic inhibition of BCL9/β-catenin-driven Wnt transcription increased antitumor responses by boosting cDC1 activation and antigen presentation of tumor-derived antigens via TAK1/NFκB/IRF1-mediated upregulation of BTK, and CXCL9/CXCR3-mediated tumor influx and crosspriming of CD8+ T cells.
Contributed by Paula Hochman
ABSTRACT: 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 hsBCL9(z96) 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-_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.
Author Info: (1) Department of Pharmacology, Minhang Hospital, and Key Laboratory of Smart Drug Delivery, Shanghai Engineering Research Center of Immune Therapy, School of Pharmacy, Fudan Unive
Author Info: (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) 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. (3) 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. (4) 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. (5) 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. (6) 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. (7) Department of Microbiology and Immunology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. (8) 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. (9) Department of Pharmacology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China. mwwang@simm.ac.cn. Research Center for Deepsea Bioresources, Sanya, China. mwwang@simm.ac.cn. Department of Chemistry, School of Science, The University of Tokyo, Tokyo, Japan. mwwang@simm.ac.cn. Engineering Research Center of Tropical Medicine Innovation and Transformation of Ministry of Education, School of Pharmacy, Hainan Medical University, Haikou, China. mwwang@simm.ac.cn. (10) Department of Pharmacology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China. zhudi@fudan.edu.cn. Shandong Academy of Pharmaceutical Science, Jinan, China. zhudi@fudan.edu.cn.
