IL-1R2 Deficiency Unleashes Neutrophil-Mediated Antitumor Potential in Sarcoma
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.
Authors
- Francesco Scavello (ORCID: https://orcid.org/0000-0002-0297-0946)
- Giovanna Grieco (ORCID: https://orcid.org/0000-0002-6863-3352)
- Giovanni Pezone
- Raffaella Bonecchi (ORCID: https://orcid.org/0000-0003-3346-5333)
- Sarah N. Mapelli (ORCID: https://orcid.org/0000-0002-0129-2055)
- Federica Riva (ORCID: https://orcid.org/0000-0002-1270-1627)
- Cecília Garlanda (ORCID: https://orcid.org/0000-0002-1510-7703)
- C Gabay
- Sébastien Jaillon (ORCID: https://orcid.org/0000-0002-5600-855X)
- Julian Swatler (ORCID: https://orcid.org/0000-0001-8710-2808)
- Andrea Mariancini (ORCID: https://orcid.org/0000-0003-1980-4423)
- Irene Di Ceglie (ORCID: https://orcid.org/0000-0002-5966-2186)
- Monica Dambra (ORCID: https://orcid.org/0000-0003-3075-4279)
- Silvia Carnevale (ORCID: https://orcid.org/0000-0002-9176-5636)
- Aycan Meral (ORCID: https://orcid.org/0000-0002-9252-6960)
- Elena Magrini (ORCID: https://orcid.org/0000-0003-1507-2325)
- Anna Rigatelli (ORCID: https://orcid.org/0000-0002-1996-899X)
- Domenico Supino (ORCID: https://orcid.org/0000-0001-9690-1791)
- Alberto Mantovani (ORCID: https://orcid.org/0000-0003-1449-0330)
- Rachele Di Donato (ORCID: https://orcid.org/0000-0003-0492-6049)
- Francesca Albano (ORCID: https://orcid.org/0000-0002-6186-1600)
- Marika Ventura
Institutions
- Humanitas University (IT)
- University of Milan (IT)
- University Hospital of Geneva (CH)
- Fondazione Humanitas per la Ricerca (IT)
- IRCCS Humanitas Research Hospital (IT)
Publication Details
- Journal
- Cancer Immunology Research
- Published
- 2026-03-13
- DOI
- https://doi.org/10.1158/2326-6066.cir-25-0651
- Primary Topic
- Immune Response and Inflammation
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- European Commission
- Associazione Italiana per la Ricerca sul Cancro