Interleukin-1 receptor type 2 (IL-1R2) deficiency is associated with resistance to mouse sarcoma development

Among the molecules that govern inflammation, cytokines belonging to the Interleukin-1 (IL-1) system play a key role by modulating the innate and adaptive immune response. In recent years, the key protumoral role of IL-1 in carcinogenesis and tumor progression has emerged. IL-1R2 is a member of the IL-1 system that acts as decoy receptor of the IL-1-mediated pathway. In human and mice, IL-1R2 is expressed by few cell types, including neutrophils and regulatory T cells. Preclinical studies demonstrated that IL-1R2 inhibits the inflammation in various pathological contexts. However, although the role of IL-1 in carcinogenesis and tumor progression is documented, the contribution of IL-1R2 in cancer has not yet been investigated. Taking advantage of IL-1R2-deficient mice, we investigated whether the absence of IL-1R2 affected cancer progression in murine primary and metastatic tumor models. Expression profile indicated that IL-1R2 was mainly expressed by bone marrow and circulating neutrophils and by intratumoral regulatory T cells. IL-1R2-deficient mice were selectively protected from tumor development in sarcoma-transplantable models, 3-MCA-induced carcinogenesis and sarcoma-induced lung metastatic model, whereas IL-1R2 deficiency was irrelevant in melanoma and adenocarcinoma models. Sarcoma protection observed in IL-1R2-deficient mice was associated with high frequency of tumor-infiltrating neutrophils, characterized by a different maturation and activation state compared to wild type counterparts. Moreover, increased neutrophil presence was also observed in bone marrow, blood and spleen and preceded the appearance of sarcoma, suggesting a possible role of IL-1R2 in emergency granulopoiesis. High neutrophil infiltration was associated with increased level at the tumor site of soluble mediators involved in neutrophil development, mobilization and recruitment. Furthermore, we demonstrated that IL-1R2 deficiency promoted neutrophil-mediated resistance to sarcoma, since genetic ablation of neutrophils resulted in exacerbated tumor growth. In agreement, we found that IL-1 signalling played a key role in protection from sarcoma development and cancer-related emergency granulopoiesis. CD8+ T and NK cells were both involved in the resistance from tumor development observed in IL-1R2-deficient mice. Finally, experiments showing neutrophilia in IL-1R2-deficient mice upon LPS-induced emergency granulopoiesis confirmed the implication of IL-1R2 in the emergency response to inflammation. Despite the known protumoral role of IL-1, we unexpectedly observed that the deficiency of the decoy receptor of the IL-1 system, IL-1R2, resulted in protection from primary and metastatic sarcoma growth in mice. The phenotype was associated with increased neutrophil recruitment and an activated phenotype. Moreover, our data highlighted the role of IL-1R2 in the regulation of emergency granulopoiesis promoted by cancer and inflammatory conditions.