AI Article Synopsis
- Conventional type 1 dendritic cells are vital for antitumor immunity, and inhibiting BCL9/BCL9L can enhance immune responses and slow tumor growth.
- Targeting BCL9/BCL9L leads to better antigen presentation in tumors by activating cDC1 and promoting their infiltration, as evidenced by the use of a novel inhibitor and knockout models.
- Single-cell transcriptomics analysis reveals that cDC1 lacking Bcl9/Bcl9l are more effective in activation and antigen presentation, suggesting that manipulating BCL9/BCL9L could improve cancer immunotherapy outcomes.
Article 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 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.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11137111 | PMC |
| http://dx.doi.org/10.1038/s41392-024-01838-9 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Tumor Vaccine Exploiting Membranes with Influenza Virus-Induced Immunogenic Cell Death to Decorate Polylactic Coglycolic Acid Nanoparticles.
ACS Nano
January 2025
Laboratory of Molecular Immunology, Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming 650031, China.
Immunogenic cell death (ICD) of tumor cells, which is characterized by releasing immunostimulatory "find me" and "eat me" signals, expressing proinflammatory cytokines and providing personalized and broad-spectrum tumor antigens draws increasing attention in developing a tumor vaccine. In this study, we aimed to investigate whether the influenza virus (IAV) is efficient enough to induce ICD in tumor cells and an extra modification of IAV components such as hemeagglutinin (HA) will be helpful for the ICD-induced cells to elicit robust antitumor effects; in addition, to evaluate whether the membrane-engineering polylactic coglycolic acid nanoparticles (PLGA NPs) simulating ICD immune stimulation mechanisms hold the potential to be a promising vaccine candidate, a mouse melanoma cell line (B16-F10 cell) was infected with IAV rescued by the reverse genetic system, and the prepared cells and membrane-modified PLGA NPs were used separately to immunize the melanoma-bearing mice. IAV-infected tumor cells exhibit dying status, releasing high mobility group box-1 (HMGB1) and adenosine triphosphate (ATP), and exposing calreticulin (CRT), IAV hemeagglutinin (HA), and tumor antigens like tyrosinase-related protein 2 (TRP2).
View Article and Find Full Text PDFExploring the comorbidity mechanisms between atherosclerosis and hashimoto's thyroiditis based on microarray and single-cell sequencing analysis.
Sci Rep
January 2025
Cardiology Department, Affiliated Hospital of Jiangxi University of Chinese Medicine, Nanchang, China.
Atherosclerosis (AS) is a chronic vascular disease characterized by inflammation of the arterial wall and the formation of cholesterol plaques. Hashimoto's thyroiditis (HT) is an autoimmune disorder marked by chronic inflammation and destruction of thyroid tissue. Although previous studies have identified common risk factors between AS and HT, the specific etiology and pathogenic mechanisms underlying these associations remain unclear.
View Article and Find Full Text PDFOptically controllable nanoregulators enable tumor-specific pro-ferroptosis lipometabolic reprogramming for in-situ adjuvant-free vaccination.
Biomaterials
January 2025
School of Life Science, Chongqing University, Chongqing, 400044, China. Electronic address:
In-situ tumor vaccination remains challenging due to difficulties in the exposure and presentation of tumor-associated neoantigens (TANs). In view of the central role of lipid metabolism in cell fate determination and tumor-immune cell communication, here we report a photo-controlled lipid metabolism nanoregulator (PLMN) to achieve robust in-situ adjuvant-free vaccination, which is constructed through hierarchically integrating photothermal-inducible arachidonate 15-lipoxygenase (ALOX15)-expressing plasmids, cypate and FIN56 into cationic liposomes. Near-infrared light (NIR) stimulation triggers on-demand ALOX15 editing and causes excessive accumulation of downstream pro-ferroptosis lipid metabolites.
View Article and Find Full Text PDFIn situ detection of individual classical MHC-I gene products in cancer.
Cancer Immunol Res
January 2025
Vanderbilt University, Nashville, TN, United States.
Tumor-specific HLA class I expression is required for cytotoxic T-cell elimination of cancer cells expressing tumor-associated or neo-antigens. Cancers downregulate antigen presentation to avoid adaptive immunity. The highly polymorphic nature of the genes encoding these proteins, coupled with quaternary-structure changes after formalin fixation, complicate detection by immunohistochemistry.
View Article and Find Full Text PDFRole of the TME in immune checkpoint blockade resistance of non-small cell lung cancer.
Cancer Drug Resist
December 2024
Department of Oncology I, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China.
Primary and secondary resistance to immune checkpoint blockade (ICB) reduces its efficacy. The mechanisms underlying immunotherapy resistance are highly complex. In non-small cell lung cancer (NSCLC), these mechanisms are primarily associated with the loss of programmed cell death-ligand 1 (PD-L1) expression, genetic mutations, circular RNA axis and transcription factor regulation, antigen presentation disorders, and dysregulation of signaling pathways.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!