Context-Dependent Role of GDF15: GDF15⁺ Tumor-Associated Macrophages Suppress OSCC Progression by Enhancing...

Area of Science:

• Immunology
• Oncology
• Molecular Biology

Background:

• Growth Differentiation Factor 15 (GDF15) neutralizing antibodies can overcome resistance to immune checkpoint blockade (ICB) in solid tumors.
• The dual role of GDF15 in cancer, promoting tumors when secreted but potentially aiding therapy when produced by immune cells, remains unclear.

Purpose of the Study:

• To investigate the context-dependent functions of GDF15 in oral squamous cell carcinoma (OSCC) using single-cell RNA-sequencing.
• To explore the role of GDF15 in macrophages and its impact on anti-tumor immunity and ICB therapy.

Main Methods:

• Single-cell RNA-sequencing of OSCC samples before and after ICB therapy.
• Utilizing Gdf15 conditional knockout mice (Gdf15fl/flLyz2Cre) to assess GDF15's role in macrophages.
• Investigating the molecular mechanisms, including NF-κB signaling, by which macrophage GDF15 influences anti-tumor responses.

Main Results:

• GDF15-expressing macrophages were enriched in ICB-sensitive OSCC post-treatment, correlating with tumor regression.
• Macrophage-specific GDF15 deficiency accelerated tumor progression by reducing CD8+ T cell infiltration.
• Macrophage GDF15 enhanced tumor cell phagocytosis and antigen cross-presentation to CD8+ T cells via NF-κB pathway activation.

Conclusions:

• The cellular source of GDF15 dictates its function: GDF15+ macrophages exert anti-tumor effects in OSCC, while secreted GDF15 has a pro-tumor role.
• Targeting secreted GDF15 with antibodies may be beneficial, while understanding macrophage GDF15's role is crucial for optimizing ICB therapy.
• These findings clarify the complex, double-edged nature of GDF15 in cancer immunology and therapy.