IL-15 suppresses colitis-associated colon carcinogenesis by inducing antitumor immunity

Abstract

IL-15 regulates the development, survival, and proliferation of multiple innate and adaptive immune cells and plays a dual role, inducing both tumor cell growth and antitumor immunity. However, the role of IL-15 in inflammation-induced cancer remains unclear. To explore this, we have compared the colon carcinoma burden of Il15^−/− and Il15rα^−/− mice with wild type (WT) mice after induction of colitis-associated colon carcinogenesis utilizing the AOM/DSS model. Compared to WT mice, Il15^−/− but not Il15rα^−/− mice showed reduced survival, along with higher tumor incidence, colon weight, and tumor size. This suggests that low affinity IL-15 signaling via the shared IL-2Rβ/γc decreases the risk for developing colitis-associated cancer. CD11c-Il15 mice, in which IL-15 expression is reconstituted in Il15^−/− mice under the control of the CD11c-promoter, showed that selective reconstitution of IL-15 in antigen-presenting cells restored the CD8⁺ T and NK cell compartments, serum levels of IFNγ, G-CSF, IL-10, and CXCL1 and reduced tumor burden. After demonstrating IL-15 expression in human colorectal cancer (CRC) cells in situ, we investigated the role of this cytokine in the modulation of key colonic oncogenic pathways in the tumor. While these pathways were found to be unaltered in the absence of IL-15, tumor transcriptome analysis showed that the loss of IL-15 upregulates key inflammatory mediators associated with colon cancer progression, such as IL-1β, IL-22, IL-23, Cxcl5, and Spp1. These findings provide evidence that IL-15 suppresses colitis-associated colon carcinogenesis through regulation of antitumor cytotoxicity, and modulation of the inflammatory tumor micromilieu.

Keywords:

• AOM/DSS
• colitis associated cancer
• cytokines
• IL-15
• immunity
• tumor

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Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Acknowledgments

We thank Hanno Ewers, Katrin Westphal, Katrin Streek, Gesine Rode, Frauke Koops, Platonas N. Selemenakis, and Ioannis L. Aivaliotis for technical assistance, Zane Orinska for helpful discussion and Leo Zeef (University of Manchester) for the microarrays analysis.

Funding

This work was supported in part by European Commission FP7 funding (INFLACARE agreement number 223151 and INSPiRE agreement number 284460) and Aristeia II from GSRT, Greece.

Authors’ Contributions

Conception and design by RB, VGG, SBP; Development of methodology by RB, ISP, OD, DAG, MP, PGF; Acquisition of data by RB, ISP, JP, OD, DAG, MP, PGF; Analysis and interpretation of data by RB, ISP, DAG, HS, KE, PGF, VGG, SBP; Writing, review, and/or revision of the manuscript by RB, MC, ISP, DAG, VGG, SBP; Study supervision by VGG, SBP.

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