IL-33/Regulatory T Cell Axis Triggers the Development of a Tumor-Promoting Immune Environment in Chronic Inflammation

Abstract

Chronic inflammation’s tumor-promoting potential is well-recognized; however, the mechanism underlying the development of this immune environment is unknown. In contrast to anti-tumor immunity in acute allergic contact dermatitis (ACD), chronic ACD is marked by a type 2 tumor-promoting immune environment. The opposite effects of chronic versus acute ACD on cancer enabled a unique paradigm to investigate how a tumor-promoting chronic inflammation develops in the first place. Epidermis-derived IL-33 upregulation and its induction of T regulatory cell accumulation in the skin preceded the transition from acute to chronic ACD and triggered the tumor-promoting immune environment in chronic ACD. Mice lacking IL-33 were protected from ACD-induced skin cancer compared to wild-type controls (p = 0.0002). IL-33’s direct signaling onto T regulatory cells was required for the development of a cancer-promoting immune environment in the skin. Notably, IL-33 to Treg signaling was also required for colorectal cancer development in colitis model (p < 0.0001). Significantly increased IL-33 and Treg marked the cancer-prone chronic inflammatory diseases of skin and colon in humans. Our findings elucidate the role of IL-33/Treg axis in the creation of tumor-promoting immune environment in chronic inflammatory diseases, which provide therapeutic targets for cancer prevention and treatment in the high-risk patients.