IL-1R2 Deficiency Unleashes Neutrophil-Mediated Antitumor Potential in Sarcoma

Abstract Interleukin-1 (IL-1) plays dual functions in cancer. It promotes cancer-related inflammation and progression, but also influences leukocyte functional activation. IL-1 receptor 2 (IL-1R2) functions as an IL-1 decoy receptor, inhibiting IL-1 activity. Here, we investigated the contribution of IL-1R2 in tuning IL-1-dependent effects in mouse models of cancer, including colorectal cancer, lung cancer, and primary and metastatic transplantable and chemically induced sarcoma. Even though the prominent role of IL-1 is pro-tumoral, IL-1R2 deficiency was selectively associated with reduced sarcoma growth, whereas it was irrelevant in other pre-clinical models investigated. IL-1R2 deficiency was associated with a massive infiltration of neutrophils in the tumor, neutrophilia, and increased extramedullary emergency granulopoiesis. Neutrophils were crucial for tumor control in IL-1R2-deficient mice. Immunophenotypic and transcriptional profiling of sarcoma-infiltrating neutrophils revealed that IL-1R2 deficiency was associated with higher expression of activation or maturation markers, and with gene expression reprogramming, with downregulation of pathways associated with pro-tumoral functions. In sarcoma patients, the IL-1R2 deficiency gene signature correlated with better clinical outcomes. Thus, this study shows that IL-1R2 tunes IL-1-driven cancer-associated emergency granulopoiesis and neutrophil functional activation to an antitumor mode in sarcomas and reveals the antitumor potential of neutrophils in this tumor.