IL-33 blockade suppresses tumor growth of human lung cancer through direct and indirect pathways in a preclinical model

Non-small-cell lung cancer (NSCLC) is the most common type in lung cancer, a leading cause of cancer-related death worldwide. Our previous study unraveled a pro-cancer function of IL-33 in fueling outgrowth and metastasis of human NSCLC cells. Herein, we determined that interfere with IL-33 activity was an effective strategy for limiting NSCLC tumor growth using a preclinical model with human NSCLC xenografts. IL-33 blockade efficiently inhibited tumor growth of NSCLC xenografts in immune-deficient mice. Mechanistically, IL-33 blockade suppressed outgrowth capacity of human NSCLC cells. Meanwhile, IL-33 blockade abrogated polarization of M2 tumor-associated macrophages (TAMs) and reduced accumulation of regulatory T cells (Tregs) in tumor microenvironments, shaping functional immune surveillance. In NSCLC patients, IL-33 expressions were positively correlated with Ki-67 proliferation index and expressions of M2 TAM- and Teg-related genes. These findings identify IL-33 as a dual-functional factor in NSCLC pathogenesis and suggest IL-33 blockade as a promising therapeutic for NSCLC patients.