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

// Kailing Wang 1, * , Shan Shan 1, 3, * , Zongjun Yang 2 , Xia Gu 1 , Yuanyuan Wang 1 , Chunhong Wang 1 and Tao Ren 1, 3 1 Department of Respiratory Medicine, East Hospital, Tongji University School of Medicine, Shanghai 200120, China 2 Department of Clinical Laboratory, Qingdao Women & Children Hospital, Qingdao 266034, China 3 Department of Respiratory Medicine, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai 200233, China * These authors have contributed equally to this work Correspondence to: Tao Ren, email: rentaosh@126.com Chunhong Wang, email: wangch910@126.com Keywords: lung cancer, IL-33, tumor-associated macrophage, regulatory T cell Abbreviations: NSCLC: non-small-cell lung cancer; TAM: tumor-associated macrophage; Treg: regulatory T cell Received: February 18, 2017      Accepted: June 18, 2017      Published: August 02, 2017 ABSTRACT 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.