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

• Published in: Oncotarget Vol. 8; no. 30; pp. 49470 - 49483
• Main Authors: Campesato, Luis Felipe, Silva, Ana Paula M, Cordeiro, Luna, Correa, Bruna R, Navarro, Fabio C P, Zanin, Rafael F, Marçola, Marina, Inoue, Lilian T, Duarte, Mariana L, Molgora, Martina, Pasqualini, Fabio, Massara, Matteo, Galante, Pedro, Barroso-Sousa, Romualdo, Polentarutti, Nadia, Riva, Federica, Costa, Erico T, Mantovani, Alberto, Garlanda, Cecilia, Camargo, Anamaria A
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 25-07-2017
• Subjects: Animals; Breast Neoplasms - genetics; Breast Neoplasms - immunology; Breast Neoplasms - pathology; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Cell Line, Tumor; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - immunology; Cytokines - metabolism; Dendritic Cells - immunology; Dendritic Cells - metabolism; Disease Models, Animal; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Immunity - genetics; Immunity, Innate - genetics; Immunomodulation; Inflammation Mediators - metabolism; Killer Cells, Natural - immunology; Killer Cells, Natural - metabolism; Mice; Mice, Knockout; NF-kappa B - metabolism; Receptors, Interleukin-1 - genetics; Research Paper; Tumor Escape - genetics; Toll/IL-1 receptors; breast cancer; innate immune sensing; immune evasion; SIGIRR/IL-1R8
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.17713

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.