IL-33/regulatory T cell axis triggers the development of a tumor-promoting immune environment in chronic inflammation
Menée à l'aide de modèles murins et d'échantillons tissulaires humains, cette étude met en évidence un mécanisme par lequel l'interleukine IL-33 et les lymphocytes T régulateurs déclenchent le développement d'un environnement immunitaire qui favorise la tumorigenèse
Chronic inflammatory diseases are well-recognized causes of cancer and account for up to 20% of all cancer deaths worldwide. However, the mechanism that initiates the development of a tumor-promoting immune environment in chronic inflammation is not known. Using mouse models of chronic skin and colon inflammation and human samples, we show IL-33 triggers the transition from tumor-suppressive immunity to chronic, tumor-promoting inflammation through a regulatory T cell-dependent mechanism. Our findings demonstrate a generalized dependency of tumor-promoting immune environments on the IL-33/Treg axis both in the skin and colon. Based on these findings, IL-33/Treg axis blockade may be an attractive therapeutic strategy for the treatment and prevention of cancers associated with chronic inflammatory diseases and potentiating the antitumor immunity induced by cancer immunotherapeutics.Chronic inflammation’s tumor-promoting potential is well-recognized; however, the mechanism underlying the development of this immune environment is unknown. Studying the transition from acute, tumor-suppressive to chronic, tumor-promoting allergic contact dermatitis (ACD) revealed how tumor-promoting chronic inflammation develops. Epidermis-derived interleukin (IL)-33 up-regulation and its induction of regulatory T cell (Treg) 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 chronic ACD and its skin cancer sequela compared with wild-type controls (P = 0.0002). IL-33’s direct signaling onto Tregs was required for the development of the tumor-promoting immune environment in the skin. IL-33–Treg signaling was also required for chronic colitis and its associated colorectal cancer development in a colitis model (P < 0.0001). Significantly increased IL-33 and Tregs marked the perilesional skin and colon in patients with cancer-prone chronic inflammatory diseases. Our findings elucidate the role of the IL-33/Treg axis in creating a tumor-promoting immune environment in chronic inflammatory diseases and suggest therapeutic targets for cancer prevention and treatment in high-risk patients.