Autor: |
Fenglian He, Zhongen Wu, Chenglong Liu, Yuanyuan Zhu, Yan Zhou, Enming Tian, Rina Rosin-Arbesfeld, Dehua Yang, Ming-Wei Wang, Di Zhu |
Jazyk: |
angličtina |
Rok vydání: |
2024 |
Předmět: |
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Zdroj: |
Signal Transduction and Targeted Therapy, Vol 9, Iss 1, Pp 1-15 (2024) |
Druh dokumentu: |
article |
ISSN: |
2059-3635 |
DOI: |
10.1038/s41392-024-01838-9 |
Popis: |
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 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. |
Databáze: |
Directory of Open Access Journals |
Externí odkaz: |
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