IL-1β/IRAK4 Axis Promotes Ovarian Tumor Development at the Mesothelium Injury Sites

Abstract

Epithelial ovarian cancer (EOC) cells seed at mesothelial inflammation or injury sites. Lack of animal models recapitulating tumor cells seeding at inflamed sites in EOC hinders mechanistic studies and therapy developments. Here, we developed a non-surgical MIM (Mesothelium Inflammation/Injury Metastasis) model that recapitulates tumor cell seeding at inflamed sites. This model captures temporal changes in tumor immune microenvironment and tumor growth allowing for deeper mechanistic and preclinical therapeutic studies of EOC in-vivo. We show here that HGS-3 high-grade murine serous EOC cells seed at needle-induced injury sites in mesothelium/peritoneal wall, forming tumors both internally and protruding outward. Using MIM model, we found that deletion of IL1R1 in mice reduced EOC cell seeding at mesothelium injury/inflamed site in WT but not IL1ra-deficient mice. Treatment of MiM mice with a novel IRAK4 inhibitor we recently developed (UR241-2) revealed an essential role for IRAK4 signaling downstream IL-1{beta}/IL-1R1 in fostering an anti-tumor inflammatory environment, and reduced tumor burden. We conclude that IRAK4 inhibitors can be more effective than IL-1/IL-1R1 targeting agents to control metastasis and peritoneal tumors, an unmet medical need in EOC recurrence. Downregulation of extracellular matrix (ECM), upregulation of neutrophil activation genes, reduced cell adhesion and migration exhibit how UR241-2 corrects ECM and immune disorders in EOC, making it less conducive to metastasis and tumorigenesis.