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  • br Overall our data suggested


    Overall our data suggested that neutrophils lacking IL-1R signaling have defective anti-bacterial functions. Together, these results underscore the importance of direct IL-1R signaling in neutrophils preventing tumor associated dysbiosis, over inflam-mation and CRC development.
    Inflammatory cytokines are emerging as regulators of the tumor microenvironment through multiple mechanisms of action. Cyto-kines are also increasingly attractive targets in cancer because they are amenable to antibody-mediated neutralization without the toxicities of common chemotherapies. As more cytokines are found to be essential for tumor development, at least in pre-clinical models, it is expected that the number of cytokine blockers tested in cancer clinical trials will increase. However, whether the efficacy of anti-cytokine therapy might be subopti-mal because of cytokine signals operating within a particular spatio-temporal context, remains unexplored.
    Previous studies have demonstrated that genetic or pharma-cologic blockade of a single pro-tumorigenic cytokine can cause an unambiguous reduction in CRC, because these TEI cytokines act on epithelial and cancer Yoda1 and drive tumor growth (Chae 
    et al., 2010; Grivennikov et al., 2009; Wang et al., 2014). Based on a vast literature implicating IL-1 signaling in the regulation of autoimmunity, inflammation, and specific induction of IL-17 pro-duction and differentiation of Th17 cells (Carmi et al., 2011; Na-kae et al., 2003; Shaw et al., 2012), we hypothesized that IL-1 driven signals would be essential for controlling TEI and thereby facilitating CRC growth. We found that whole body and hemato-poietic cell-specific IL-1R1 ablation did decrease expression of TEI cytokines, but unexpectedly caused very limited, if any, decrease in CRC. This presented us with a conundrum of why inactivation of IL-1R signaling in the hematopoietic system did not tame CRC, despite a reduction in pro-tumorigenic cytokines whose inactivation reproducibly reduces CRC in a variety of experimental conditions (Blatner et al., 2012; Grivennikov et al., 2012; Kirchberger et al., 2013). Given the multifaceted roles of IL-1R1 and the fact that IL-1R1 is expressed by virtually all cell types in the body, it was conceivable that IL-1 signaling may have opposing roles in different cell types. In this work we showed that in the CRC tumor microenvironment, IL-1 signaling plays distinct roles, depending on cell type, and established the cellular and molecular mechanisms governing how this particular cytokine regulated multipronged processes during intestinal tumorigenesis.
    Analysis of epithelial-specific IL-1R1 deletion revealed a decrease in CRC tumor multiplicity, slower proliferation of early tumor seeds, and decreased activation of NF-kB. NF-kB is an essential regulator of cell survival and proliferation, and its inac-tivation in intestinal epithelial cells by deletion of IKKb kinase during the development of colitis-associated cancer decreases tumor multiplicity (Greten et al., 2004). These observations are in line with reports that IL-1a and IL-1b stimulate growth in colon cancer cell lines in vitro and in xenograft transplants in vivo (Voronov et al., 2003; Holen et al., 2016). While NF-kB can be activated by a plethora of stimuli, IL-1R signaling may be essen-tial for activating NF-kB in CRC because IL-1a and IL-1b are rapidly released by transformed and stressed cells, as well as by cells stimulated with microbes infiltrating early tumors. IL-1 signaling in epithelium regulated early CRC, while being dispens-able for the expression of inflammatory cytokines, indicating that IL-1 signaling controlled CRC in an inflammation-independent manner.
    In T cells, IL-1 signaling regulated CRC in an inflammation-dependent manner. Lymphoid cells, including T cells and ILC3, are important producers of IL-17A and other TEI cytokines dur-ing host defense and chronic inflammation. These lymphoid cells infiltrate CRC tumors and their increased presence correlates with poor prognosis in CRC patients, according to CRC ‘‘Immu-noscore’’ (Bindea et al., 2013; Tosolini et al., 2011). Here we found that IL-1 signaling in T cells was essential for the produc-tion of IL-17A and IL-22 cytokines in CRC tumors, consistent with what has been observed in other inflammatory conditions in mice and humans (Shaw et al., 2012; Zhou and Littman,