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

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.

Tuning inflammation and immunity by the negative regulators IL‐1R2 and IL‐1R8

“…IL‐1R8‐deficient mice were protected from the development of breast cancer in a genetic model (MMTV‐neu) and the number of lung metastasis was reduced. In vitro and in vivo evidences demonstrated that IL‐1R8 in tumor cells was responsible for shaping the tumor microenvironment and IL‐1R8 deficiency was associated with higher frequency of DCs, NK cells and CD8 + T cells and lower frequency of TAMs . In line with this, RNAseq analysis in 1102 clinical samples of breast tumors revealed that high IL‐1R8 expression was associated with a non‐T cell inflamed molecular signature, lower expression level of proinflammatory cytokines and chemokines, DC and NK cell metagenes, components of the peptide‐presenting machinery, cytolytic enzymes and type I IFN‐induced genes.…”

“…In line with this, RNAseq analysis in 1102 clinical samples of breast tumors revealed that high IL‐1R8 expression was associated with a non‐T cell inflamed molecular signature, lower expression level of proinflammatory cytokines and chemokines, DC and NK cell metagenes, components of the peptide‐presenting machinery, cytolytic enzymes and type I IFN‐induced genes. Collectively, these data indicate that IL‐1R8 expression in breast tumors represents a novel immunomodulatory mechanism, affecting the mobilization and activation of immune cells and therefore tumor growth and metastatization . These findings have important therapeutic implications, since the blockade of IL‐1R8 in breast tumor cells may represent a way to restore the innate immune response and T‐cell trafficking and activation in the tumor microenvironment.…”

“…Finally, colon tumorigenesis was associated with reduced expression of IL‐1R8 on the intestinal cell surface, where an inactive mutant form of IL‐1R8 was generated by alternative splicing . On the contrary, in breast cancer, IL‐1R8 was identified as an upregulated gene in transformed cells compared to normal epithelial cells, in both cell lines and RNASeq data of primary breast tumors …”

“…91 On the contrary, in breast cancer, IL-1R8 was identified as an upregulated gene in transformed cells compared to normal epithelial cells, in both cell lines and RNASeq data of primary breast tumors. 104 It has been proposed that the zinc finger protein SP1 normally binds to the proximal promoter of IL-1R8 inducing gene transcription in epithelial cells and human primary monocytes and neutrophils. 93 Cell stimulation with LPS causes inhibition of SP1 binding to IL-1R8 promoter via activation of p38, which is downstream of TLR4.…”

Effects of tumor grade and dexamethasone on myeloid cells in patients with glioma

“…Tumor associated macrophages (TAMs), accounting for ~ 20–30% of the cells in the GBM tumor mass, 2 express soluble factors and surface molecules that prevent immune surveillance by endogenous T and NK cells, and shut down crosstalk between the adaptive and innate immune systems. 3-5 Novel therapies that circumvent this suppressive milieu by blocking the recruitment or polarization of TAMs 6,7 are complicated by the paucity of markers that discriminate dysfunctional cells 8 and a poor understanding of the tumor-derived factors that influence their phenotype or trafficking. 9,10 Furthermore, gene expression analysis suggests that TAMs differ across grades of glioma 11,12 and regions within heterogeneous GBM tumors, 13 although it is not clear how these factors impact TAMs phenotypically and functionally.…”