Gut epithelial Interleukin-17 receptor A signaling can modulate distant tumors growth through microbial regulation

Area of Science:

• Oncology
• Immunology
• Microbiology

Background:

• Interleukin-17 (IL-17) signaling regulates gut immunity and microbes but can also promote tumor growth.
• The role of gut IL-17-IL-17 receptor A (IL-17RA) signaling and microbial influence on distant tumors is not well understood.

Purpose of the Study:

• To investigate how gut dysbiosis, driven by IL-17RA deletion, affects pancreatic and brain tumor growth.
• To elucidate the mechanisms by which microbial-dependent IL-17 signaling influences tumor progression and therapy response.

Main Methods:

• Systemic or gut epithelial deletion of IL-17RA in mouse models.
• Induction of gut dysbiosis and assessment of tumor growth in pancreatic and brain tumors.
• Analysis of Th17 cells, B cells, and DUOX2 signaling in tumor microenvironments.
• Evaluation of targeted microbial ablation combined with IL-17RA inhibition.

Main Results:

• Deletion of IL-17RA in the gut led to gut dysbiosis and accelerated growth of pancreatic and brain tumors.
• Increased Th17 cells and B cells were observed, which migrated to distant tumors.
• Microbial-dependent IL-17 signaling enhanced DUOX2 signaling within tumor cells.
• Targeted microbial ablation sensitized tumors to IL-17RA inhibition, overcoming therapeutic resistance.

Conclusions:

• Gut microbial regulation of IL-17-IL-17RA signaling significantly impacts distant tumor growth and progression.
• Understanding the complex interplay between the gut microbiome, IL-17 signaling, and tumor behavior is crucial for effective cancer therapy.
• Targeting microbial pathways offers a strategy to overcome resistance to IL-17RA-targeted therapies.