AEBP1 drives fibroblast-mediated T cell dysfunction in tumors.

Area of Science:

• Immunology
• Oncology
• Molecular Biology

Background:

• T cell dysfunction is a key mechanism of tumor immune evasion, limiting the efficacy of cancer immunotherapy.
• Understanding the molecular drivers of T cell dysfunction is critical for developing novel therapeutic strategies.

Purpose of the Study:

• To investigate the role of Adipocyte Enhancer-Binding Protein 1 (AEBP1) in T cell dysfunction within the tumor microenvironment.
• To identify AEBP1 as a potential therapeutic target for enhancing anti-tumor immunity.

Main Methods:

• RNA-sequencing analysis of human colon adenocarcinoma and triple-negative breast cancer tissues.
• Single-cell RNA sequencing to identify AEBP1-expressing cells.
• Fibroblast-specific AEBP1 deletion in mouse models.
• Molecular docking-based virtual screening to identify AEBP1 inhibitors.
• Assessment of therapeutic efficacy in syngeneic mouse models.

Main Results:

• AEBP1 expression positively correlates with T cell dysfunction and poor patient prognosis in human cancers.
• Cancer-associated fibroblasts (CAFs) are identified as the primary source of AEBP1.
• AEBP1 deletion in fibroblasts enhances T cell cytotoxicity and suppresses tumor growth.
• AEBP1-CKAP4 interaction on CAFs activates AKT/PD-L1 signaling, promoting T cell dysfunction.
• A novel drug, Chem-0199, disrupts AEBP1-CKAP4 interaction, enhancing anti-tumor immunity.
• Combined genetic or pharmacological AEBP1 inhibition with immune checkpoint blockade shows synergistic anti-tumor effects.

Conclusions:

• AEBP1 is a critical regulator of CAF-mediated T cell dysfunction in cancer.
• Targeting AEBP1 presents a promising therapeutic strategy to overcome tumor immune evasion and improve immunotherapy outcomes.