134 Functional role of merkel cell polyomavirus T-antigen regulated microRNAs in merkel cell carcinoma

Abstract

Chronic inflammation is a well-characterized driver of cancer in the skin and other epithelial organs; however, the mechanism underlying the development of cancer-promoting chronic inflammation is unknown. We previously showed chronic allergic contact dermatitis (ACD) is a type 2 inflammatory disease and potent inducer of squamous cell carcinoma in mice and humans. In contrast, acute ACD, a common skin inflammatory condition, is marked by type 1 inflammation, including T helper 1, cytotoxic T, and NK cells, which inhibit cancer development. The opposite effects of chronic versus acute ACD on cancer provide a unique paradigm to investigate how cancer-promoting chronic inflammation develops. To determine the mechanism underlying the transition from acute to chronic ACD, we examined the epithelium-derived cytokines, IL-33, TSLP, and IL-25, that are master drivers of type 2 inflammation in barrier organs. IL-33 expression markedly increased during the transition from acute to chronic ACD, initiating tumor-promoting, type 2 inflammation in chronic ACD. Mice lacking IL-33 or IL-33 receptor (ST2) were protected from ACD-induced skin cancer compared to wild-type controls and IL-33 was required for the progression of inflammatory bowel disease-induced colorectal cancer. Notably, IL-33s direct effect on T regulatory cells was required for the development of a cancer-promoting immune environment in the skin and colon. Our findings elucidate a novel mechanism underlying the formation of a tumorinitiating immune environment in chronic inflammatory diseases and yield novel targets for cancer treatment and prevention in chronic inflammatory contexts.