Abstract
IL-27 regulates inflammatory diseases by exerting a pleiotropic impact on immune cells. In cancer, IL-27 restricts tumor growth by acting on tumor cells directly, while its role in the tumor microenvironment is still controversially discussed. To explore IL-27 signaling in the tumor stroma, we used a mammary carcinoma syngraft approach in IL27Rα-deficient mice. Tumor growth in animals lacking IL27Rα was markedly reduced. We noticed a decrease in immune cell infiltrates, enhanced tumor cell death, and fibroblast accumulation. However, most striking changes pertain the tumor vasculature. Tumors in IL27Rα-deficient mice were unable to form functional vessels. Blocking IL-27-STAT1 signaling in endothelial cells in vitro provoked an overshooting migration/sprouting of endothelial cells. Apparently, the lack of the IL-27 receptor caused endothelial cell hyper-activation via STAT1 that limited vessel maturation. Our data reveal a so far unappreciated role of IL-27 in endothelial cells with importance in pathological vessel formation.
Highlights
Interleukin 27 (IL-27) is a heterodimeric cytokine of the IL-12 family, composed of IL-27p28 and Epstein–Barr virus (EBV)-induced gene 3 (EBI3)
We suggest a third scenario in tumors, where compromised tumor vessels can be rendered even more dysfunctional, to again restrict tumor growth
In support of this hypothesis two recent studies showed that a loss of deltalike 4 (Dll4) increased in non-functional and convolute vessels, thereby reducing tumor growth [39, 40]
Summary
Interleukin 27 (IL-27) is a heterodimeric cytokine of the IL-12 family, composed of IL-27p28 and Epstein–Barr virus (EBV)-induced gene 3 (EBI3). It is mainly expressed and secreted by antigen presenting cells. IL-27 signals via a receptor complex, consisting of IL27Rα and the signaltransducing glycoprotein 130 (gp130) [1, 2]. Specificity of IL-27 signaling depends on IL27Rα. IL27Rα is expressed on many immune and stromal cells, whereas it is nearly absent on B cells and neutrophils. Once IL-27 binds to its receptor complex, mainly janus kinase (JAK) and downstream signal transducer and activator of transcription (STAT) are activated [3, 4]
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