• 2019-07
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  • br Neutrophils but not monocytes or macrophages were


    Neutrophils but not monocytes or macrophages were essential to deter tumor-infiltrating bacteria and dampen CRC promoting inflammation. Neutrophils represent an important component of the tumor microenvironment, where they can be immunosuppressive as a form of myeloid derived suppressor Ceruletide or directly tumor promoting or anti-tumorigenic (Fridlender et al., 2009; Gabrilovich and Nagaraj, 2009). While neutrophils are a key component of anti-microbial defense, here we found a tumor specific, anti-microbial role for neutrophils in cancer. Previous work on Il1r1 / mice shows defective neutrophil recruitment and higher susceptibility to infection, with no change in bacterial killing assessed primarily in macrophages (Miller et al., 2006). Here, we found that while lack of IL-1R on neutro-phils did not alter neutrophil recruitment and its ability to form NET’s, however, it led to defective bacterial killing. Thus, neutro-phil-specific IL-1 signaling is critical for preventing tumor-associ-ated dysbiosis, TEI and CRC, where bacteria are invasive due to the increased epithelial permeability and decreased mucus coverage. Significant alterations of commensal microbiota are present in mouse mutants devoid of IL-18 signaling and in various mutants affecting the inflammasome pathway (Elinav et al., 2011; Franchi et al., 2010) essential for IL-1b and IL-18 cytokine processing and activation, but altered microbiota have not been found in mice with global IL-1R1 deficiency.
    The IL-1 pathway has been extensively studied in the context of cancer, but often using cell-line-based non-autochthonous models, immunodeficient mice, or cancer models where epithelial surfaces are not rich in microbes. Levels of IL-1b are elevated in multiple cancers in human and mouse models, including colon, gastric, breast, non-small-cell lung carcinoma, and melanomas (Elaraj et al., 2006). Genetic inactivation of IL-1R1 or caspase 1, a key enzyme in IL-1b processing, reduced tumorigenesis in a two-step skin cancer model (Drexler et al., 2012). Inactivation of IL-1a and MyD88 reduces liver carcinogenesis in DEN model (Sa-kurai et al., 2008). Blocking IL-1 signaling in human breast cancer
    xenografts or a mouse model of breast cancer results in changes in tumor growth and metastatic spread, and also in decreased infiltration by myeloid CD11b+Gr1+ cells (Dagenais et al., 2017; Holen et al., 2016). Neutrophils and IL-1 signaling are critical for breast cancer metastasis but not primary tumor growth (Coffelt et al., 2015), and environmental and dietary factors can drive inflammasome/IL-1 dependent breast cancer (Kolb et al., 2016). Furthermore, in transplantable B16 melanoma and prostate can-cer models, IL-1b was found to be essential for invasiveness and metastatic growth while the same function has been assigned to IL-1a in breast cancer (Voronov et al., 2003). IL-1a and MyD88 signaling drive skin tumorigenesis (Cataisson et al., 2012); how-ever, in the model of MCA-induced fibrosarcoma, IL-1a is essen-tial for activation of antitumor responses (Elkabets et al., 2009). Moreover IL-1 can play a role of a ‘‘danger signal,’’ when released from necrotizing cells (Ghiringhelli et al., 2009). Still, it remains to be determined whether IL-1 exerts its pro-tumorigenic signaling by induction of TEI or whether IL-1 signaling is largely autonomous to cancer cells. Recently, an IL-1a neutralizing antibody was tested in clinical trials for advanced CRC (Hickish et al., 2017); meanwhile a complete blockade of IL-1 signaling has been pro-posed but not thoroughly examined.
    Propelled by numerous studies implicating inflammatory IL-1 signaling in cancer, several clinical studies with IL-1 antagonists as monotherapies and combination therapies for human cancers are underway. Our results, however, suggest that a more cautious Ceruletide approach may be required when considering the use of IL-1 blockade in CRC and urges caution against a ‘‘one size fits all’’ global blockade of IL-1R signaling. We propose that in some microbe-rich cancers a complete inhibition of IL-1R signaling would not be as beneficial as specific blockade of this axis in T cells or epithelial cells, for example via antibody-based ap-proaches that deliver IL-1 blockers specifically to T cells. Such next-generation approaches will allow blocking IL-1R signaling only in ‘‘pro-tumorigenic’’ cell types, while preserving ‘‘anti-tumor-igenic,’’ protective signaling. Alternatively, approaches aimed at enhancing intra-tumoral anti-bacterial functions or depleting potentially pathogenic microbiota should be considered along with IL-1R signaling blockade. Finally, the role of individual IL-1a and IL-1b ligands and the potential for their neutralization over complete IL-1R blockade needs to be further assessed. r>