High IL-1R8 expression in breast tumors promotes tumor growth and contributes to impaired antitumor immunity
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Luis Felipe Campesato1,2,3, Ana Paula M. Silva1, Luna Cordeiro4, Bruna R. Correa2, Fabio C.P. Navarro2, Rafael F. Zanin5, Marina Marçola6, Lilian T. Inoue2, Mariana L. Duarte2, Martina Molgora4, Fabio Pasqualini4, Matteo Massara4, Pedro Galante2, Romualdo Barroso-Sousa7, Nadia Polentarutti4, Federica Riva8, Erico T. Costa1,2, Alberto Mantovani4,9, Cecilia Garlanda4 and Anamaria A. Camargo1,2
1Ludwig Institute for Cancer Research, São Paulo, São Paulo, Brazil
2Molecular Oncology Center, Hospital Sírio-Libanês, São Paulo, São Paulo, Brazil
3Graduate Program in Biochemistry, Institute of Chemistry, University of São Paulo, São Paulo, Brazil
4Humanitas Clinical and Research Center, Rozzano, Italy
5Cellular and Molecular Immunology Laboratory, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil
6Institute of Biosciences, University of São Paulo, São Paulo, Brazil
7Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
8Department of Veterinary Pathology, University of Milan, Milan, Italy
9Humanitas University, Rozzano, Italy
Anamaria A. Camargo, email: email@example.com
Cecilia Garlanda, email: firstname.lastname@example.org
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
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.
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