title: 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 ofIl15-/-andIl15rα-/-mice with wild type (WT) mice after induction of colitis-associated colon carcinogenesis utilizing the AOM/DSS model. Compared to WT mice,Il15-/-but notIl15rα-/-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-Il15mice, in which IL-15 expression is reconstituted inIl15-/-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) cellsin 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 asIL-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.
authors.affiliation: Institute of Inflammation and Repair and MCCIR; University of Manchester ; Manchester, UK ; Priority Area Asthma and Allergies; Research Center Borstel ; Borstel, Germany.
authors.forename: Rajia
authors.initials: R
authors.lastname: Bahri
authors.affiliation: Molecular Carcinogenesis Group; Department of Histology & Embryology; School of Medicine; University of Athens ; Athens, Greece.
authors.forename: Ioannis S
authors.initials: IS
authors.lastname: Pateras
authors.affiliation: Priority Area Asthma and Allergies; Research Center Borstel ; Borstel, Germany.
authors.forename: Orietta
authors.initials: O
authors.lastname: D'Orlando
authors.affiliation: Priority Area Asthma and Allergies; Research Center Borstel ; Borstel, Germany.
authors.forename: Diego A
authors.initials: DA
authors.lastname: Goyeneche-Patino
authors.affiliation: Institute of Inflammation and Repair and MCCIR; University of Manchester ; Manchester, UK.
authors.forename: Michelle
authors.initials: M
authors.lastname: Campbell
authors.affiliation: Priority Area Asthma and Allergies; Research Center Borstel ; Borstel, Germany.
authors.forename: Julia K
authors.initials: JK
authors.lastname: Polansky
authors.affiliation: Institute of Inflammation and Repair and MCCIR; University of Manchester ; Manchester, UK.
authors.forename: Hilary
authors.initials: H
authors.lastname: Sandig
authors.affiliation: Molecular Carcinogenesis Group; Department of Histology & Embryology; School of Medicine; University of Athens ; Athens, Greece.
authors.forename: Marilena
authors.initials: M
authors.lastname: Papaioannou
authors.affiliation: Molecular Carcinogenesis Group; Department of Histology & Embryology; School of Medicine; University of Athens ; Athens, Greece.
authors.forename: Kostas
authors.initials: K
authors.lastname: Evangelou
authors.affiliation: Molecular Carcinogenesis Group; Department of Histology & Embryology; School of Medicine; University of Athens ; Athens, Greece ; 2nd Department of Pathology; University of Athens Medical School; "Attikon" University Hospital ; Athens, Greece.
authors.forename: Periklis G
authors.initials: PG
authors.lastname: Foukas
authors.affiliation: Molecular Carcinogenesis Group; Department of Histology & Embryology; School of Medicine; University of Athens ; Athens, Greece ; Biomedical Research Foundation; Academy of Athens ; Athens, Greece ; Faculty Institute for Cancer Sciences; University of Manchester; Manchester Academic Health Science Centre ; Manchester, UK.
authors.forename: Vassilis G
authors.initials: VG
authors.lastname: Gorgoulis
authors.affiliation: Institute of Inflammation and Repair and MCCIR; University of Manchester ; Manchester, UK.
authors.forename: Silvia
authors.initials: S
authors.lastname: Bulfone-Paus
keywords: AOM/DSS; IL-15; colitis associated cancer; cytokines; immunity; tumor