High IL-1R8 expression in breast tumors promotes tumor growth and contributes to impaired antitumor immunity

// Luis Felipe Campesato 1, 2, 3 , Ana Paula M. Silva 1 , Luna Cordeiro 4 , Bruna R. Correa 2 , Fabio C.P. Navarro 2 , Rafael F. Zanin 5 , Marina Marçola 6 , Lilian T. Inoue 2 , Mariana L. Duarte 2 , Martina Molgora 4 , Fabio Pasqualini 4 , Matteo Massara 4 , Pedro Galante 2 , Romualdo Barroso-Sousa 7 , Nadia Polentarutti 4 , Federica Riva 8 , Erico T. Costa 1, 2 , Alberto Mantovani 4, 9 , Cecilia Garlanda 4 and Anamaria A. Camargo 1, 2 1 Ludwig Institute for Cancer Research, São Paulo, São Paulo, Brazil 2 Molecular Oncology Center, Hospital Sírio-Libanês, São Paulo, São Paulo, Brazil 3 Graduate Program in Biochemistry, Institute of Chemistry, University of São Paulo, São Paulo, Brazil 4 Humanitas Clinical and Research Center, Rozzano, Italy 5 Cellular and Molecular Immunology Laboratory, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil 6 Institute of Biosciences, University of São Paulo, São Paulo, Brazil 7 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA 8 Department of Veterinary Pathology, University of Milan, Milan, Italy 9 Humanitas University, Rozzano, Italy Correspondence to: Anamaria A. Camargo, email: aacamargo@mochsl.org.br Cecilia Garlanda, email: cecilia.garlanda@humanitasresearch.it Keywords: breast cancer, SIGIRR/IL-1R8, Toll/IL-1 receptors, innate immune sensing, immune evasion Received: January 25, 2017      Accepted: April 25, 2017      Published: May 09, 2017 ABSTRACT Tumors develop numerous strategies to fine-tune inflammation and avoid detection and eradication by the immune system. The identification of mechanisms leading to local immune dysregulation is critical to improve cancer therapy. We here demonstrate that Interleukin-1 receptor 8 (IL-1R8 - previously known as SIGIRR/TIR8), a negative regulator of Toll-Like and Interleukin-1 Receptor family signaling, is up-regulated during breast epithelial cell transformation and in primary breast tumors. IL-1R8 expression in transformed breast epithelial cells reduced IL-1-dependent NF-κB activation and production of pro-inflammatory cytokines, inhibited NK cell activation and favored M2-like macrophage polarization. In a murine breast cancer model (MMTV-neu), IL-1R8-deficiency reduced tumor growth and metastasis and was associated with increased mobilization and activation of immune cells, such as NK cells and CD8 + T cells. Finally, immune-gene signature analysis in clinical specimens revealed that high IL-1R8 expression is associated with impaired innate immune sensing and T-cell exclusion from the tumor microenvironment. Our results indicate that high IL-1R8 expression acts as a novel immunomodulatory mechanism leading to dysregulated immunity with important implications for breast cancer immunotherapy.