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IL-15 is an inflammatory mediator in the tumor microenvironment
© Anthony et al. 2015
Published: 4 November 2015
Previous studies have shown that activation of the Stimulator of Interferon Genes (STING) pathway is important for regulating type I Interferons (IFN) in tumors. Furthermore, tumor DNA induces IL-15 and IL-15Rα mRNA in cultured dendritic cells (DC) in a STING-dependent manner. Since we have recently shown type I IFNs induce soluble IL-15Rα/IL-15 complexes (sIL-15 complexes), we set out to determine if sIL-15 complexes are produced in tumor microenvironment and are regulated by STING signaling. To determine if STING induces sIL-15 complexes, mice were given STING agonists (c-di-GMP) either i.v. or i.p. One day later, sIL-15 complexes were increased in serum and splenic homogenates of STING-treated mice. In addition, STING agonists directly induced sIL-15 complexes in BM-derived DCs. To examine sIL-15 complexes in the tumor microenvironment, B16-F10 tumors of various sizes were isolated from mice and sIL-15 complexes were measured in homogenates from tumors, draining lymph nodes, and spleen. Interestingly, levels of sIL-15 complexes were high in homogenates from small tumors (less than 100mm2) and their draining lymph nodes but low in larger tumors. These findings suggest IL-15 is an inflammatory factor produced during early tumor development. To investigate the role of IL-15 within the tumor microenvironment, we analyzed tumor growth in mice conditionally deleted of IL-15Rα (IL-15Rα floxed X ER-Cre Tg). Unlike IL-15Rα-/- mice, this model system allows examination of lymphocytes that have developed in the presence of IL-15 signals. In mice conditionally deleted of IL-15Rα (Tamoxifen-treated IL-15Rα floxed X ER-Cre Tg mice), tumor growth was increased compared to control mice (Tamoxifen treated IL-15Rα floxed mice). Overall, these studies suggest that IL-15 is a component of the inflammatory milieu of the tumor microenvironment that likely contributes to native anti-tumor responses. This work was supported by a seed fund from the Center for Inflammation and Cancer at the MD Anderson Cancer Center and a Cancer Prevention and Research Institute of Texas Research Training Award.
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.