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 Il15ra ¡/¡ 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 Il15ra ¡/¡ 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-2Rb/gc 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 C T and NK cell compartments, serum levels of IFNg, 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-1b, 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.

High dose CD11c-driven IL15 is sufficient to drive NK cell maturation and anti-tumor activity in a trans-presentation independent manner

“…This conclusion is in line with literature reporting prevention of lung or breast cancer metastasis being dependent on mature KLRG1 + NK cell numbers 27 32 and IFNγ-mediated mechanisms 33 . Furthermore, our findings on the role of IL15-driven NK cell-mediated inhibition of tumor growth are in accordance with our previous report using the DSS/AOM model of colitis-associated colon carcinogenesis 34 and the findings that IL15 induces very densely granulated NK cells that can eliminate large established solid tumors in the absence of T and B cells 35 . In this latter model expression of the IL15Rα on cancer cells was needed to efficiently induce granulated NK cells, and expression on host stromal cells was essential to prevent tumor relapse.…”

Cytokine-Induced Modulation of Colorectal Cancer

“…Colorectal cancer patients with genomic deletion of IL15 have a significantly higher risk of tumor recurrence and show reduced survival compared with patients with intact IL15 ( 19 ). Moreover, IL-15 is expressed in human CRC cells in situ ( 120 ).…”

Mechanistic roles of epithelial and immune cell signaling during the development of colitis-associated cancer

“…In fact, IL-10 KO mice are highly susceptible to UC and CAC due to uncontrolled inflammation in the colon (139, 140). IL-15 suppresses CAC by promoting anti-tumor immunity by CD8 + T cells and NK cells (141). Several studies have shown that either inhibition of a combination of proinflammatory cytokines, cytokine receptors or addition of recombinant anti-inflammatory cytokines will likely reduce the CAC in IBD patients.…”