IL1R2 Deficiency Unleashes Neutrophil-Mediated Antitumor Potential in Sarcoma.

Area of Science:

• Immunology
• Oncology
• Molecular Biology

Background:

• Interleukin-1 (IL-1) exhibits dual roles in cancer, potentially promoting inflammation and progression while also influencing immune cell activation.
• Interleukin-1 receptor 2 (IL-1R2) acts as a decoy receptor, antagonizing IL-1 activity.
• The specific role of IL-1R2 in modulating IL-1-driven effects in various cancer models requires further investigation.

Purpose of the Study:

• To investigate the role of IL-1R2 in regulating IL-1-dependent effects across different mouse cancer models.
• To determine the impact of IL-1R2 deficiency on tumor growth, immune cell infiltration, and neutrophil function in sarcomas.
• To explore the clinical relevance of IL-1R2 deficiency in human sarcoma patients.

Main Methods:

• Utilized mouse models of colorectal cancer, lung cancer, and chemically induced and transplantable sarcomas.
• Assessed tumor growth, immune cell infiltration (specifically neutrophils), and extramedullary granulopoiesis in IL-1R2-deficient and wild-type mice.
• Performed immunophenotypic and transcriptional profiling of tumor-infiltrating neutrophils.
• Analyzed gene expression signatures in human sarcoma patient data.

Main Results:

• IL-1R2 deficiency selectively reduced sarcoma growth, with no significant impact on other investigated cancer models.
• IL-1R2 deficiency led to massive neutrophil infiltration in tumors (neutrophilia) and increased emergency granulopoiesis.
• Neutrophils in IL-1R2-deficient sarcomas showed enhanced activation markers and gene expression reprogramming towards antitumor functions.
• A gene signature associated with IL-1R2 deficiency correlated with improved clinical outcomes in human sarcoma patients.

Conclusions:

• IL-1R2 plays a critical role in tuning IL-1-driven emergency granulopoiesis and neutrophil activation in sarcomas.
• IL-1R2 deficiency redirects neutrophil responses to an antitumor mode specifically in sarcomas.
• Neutrophils possess significant antitumor potential in sarcomas, modulated by IL-1R2 activity.
• Targeting IL-1R2 may represent a therapeutic strategy to enhance antitumor immunity in sarcoma.