| IL-33 is a member of the IL-1 cytokine family,which mainly induced type II immune response,but increasing evidence suggests that IL-33 also regulates tumor development In gastric cancer and cervical cancer and malignant myeloma the expression of IL-33 is associated with poor prognosis,while in lung cancer,liver cancer and melanoma patients,IL-33 expression inhibits tumor progression.These conflicting results indicate that the function of IL-33 in the tumor environment has tissue specificity.Therefore,to understand the effect of IL-33 in tumor development under different condition,the detailed mechanisms by which IL-33 modulates tumor development in specific conditions need more investigation.Using the experimental breast cancer pulmonary metastasis model builded by 4T1-luc cells,we found that IL-33 administration effectively inhibits the pulmonary metastasis of breast cancer and prolongs the survival in a ST2-dependent manner.Furthermore,IL33 expression is positively correlated with improved prognosis in breast cancer patients.We also found that NK cells plays the dominate roles in the IL-33 induced tumor suppression.In our model,IL-33 promotes the production of TNF-a by macrophages,which increases ST2 expression on NK cells and is pivotal in IL-33-induced NK cell activation.IL-33 treatment also facilitates the production of CCL5 in the lung by eosinophils and CD8+T cells,which mediates the recruitment of NK cells to the tumor microenvironment.The systemic activation and local recruitment of NK cells result in potent tumor rejection in the lung.We described a novel mechanism for IL-33-mediated suppression of the tumor metastasis,where IL-33 administration substantially enhanced the activation and specific recruitment of NK cells to the tumor site in the 4T1 breast cancer pulmonary metastatic model.Our study confirmed the anti-tumor function of IL-33,as well as its modulation of the TME,thus provides potential therapeutic strategies for targeting metastatic tumor. |
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