Epithelial YPEL3 Modulates CD8⁺ T-Cell Infiltration and Tumor Progression Through CREB1-CXCL16 Signaling in HNSCC

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• Yippee-like 3 (YPEL3) is involved in cancer regulation, but its function in head and neck squamous cell carcinoma (HNSCC) is unknown.
• Understanding YPEL3's role is crucial for developing novel HNSCC therapies.

Purpose of the Study:

• To investigate the expression, prognostic value, and immune relevance of YPEL3 in HNSCC.
• To elucidate the molecular mechanisms underlying YPEL3's function in HNSCC.

Main Methods:

• Integrated analysis of pan-cancer data, TCGA/GEO transcriptomes, DNA methylation, and single-cell RNA sequencing.
• In vitro and in vivo functional assays (proliferation, migration, invasion, apoptosis, tumor growth).
• Bulk transcriptomics, TIMER analysis, and co-culture assays to explore immune cell infiltration and molecular pathways.

Main Results:

• YPEL3 is downregulated in HNSCC and correlates with better overall survival.
• YPEL3 suppresses tumor proliferation, migration, and invasion, and promotes apoptosis.
• High YPEL3 expression enhances CD8+ T cell infiltration and function via the CXCL16-CXCR6 axis, regulated by CREB1.

Conclusions:

• YPEL3 functions as a tumor suppressor in HNSCC.
• YPEL3 mediates epithelial-immune crosstalk, linking epithelial states to antitumor immunity through the CREB1/CXCL16/CXCR6 axis.