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 <i>Il15^-/-</i> and <i>Il15r</i>α <i>^-/-</i> mice with wild type (WT) mice after induction of colitis-associated colon carcinogenesis utilizing the AOM/DSS model. Compared to WT mice, <i>Il15^-/-</i> but not <i>Il15r</i>α <i>^-/-</i> 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. <i>CD11c-Il15</i> mice, in which IL-15 expression is reconstituted in <i>Il15^-/-</i> 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 <i>in situ</i>, 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 <i>IL-1</i>β<i>, IL-22</i>, <i>IL-23, Cxcl5, and Spp1.</i> These findings provide evidence that IL-15 suppresses colitis-associated colon carcinogenesis through regulation of antitumor cytotoxicity, and modulation of the inflammatory tumor micromilieu.