Ionizing Radiation-Induced Tumor Cell-Derived Microparticles Prevent Lung Metastasis by Remodeling the Pulmonary Immune Microenvironment

Abstract

The majority of cancer-related deaths are attributed to metastasis rather than localized primary tumor progression. However, the factors that regulate the premetastatic niche (PMN) and metastasis have not yet been clearly elucidated. We investigated the antimetastatic effects of irradiated tumor cell-derived microparticles (RT-MPs) and highlighted the role of innate immune cells in PMN formation. Mice were treated 3 times with isolated RT-MPs, followed by tumor cell injection via the tail vein. The hematoxylin and eosin staining was performed to assess the number of tumor nodules in the lungs, and in vivo luciferase-based noninvasive bioluminescence imaging was conducted to detected tumor burden. The mechanisms of RT-MPs mediated PMN formation was evaluated using flow cytometry, transwell assay, and reverse transcription-polymerase chain reaction. RT-MPs inhibited tumor cell colonization in the lungs. Neutrophils phagocytosed RT-MPs and secreted CCL3 and CCL4, which induced monocytes chemotaxis and maturation into macrophages. RT-MPs promoted the transition of neutrophils and macrophages into antitumor phenotypes, hence inhibiting cancer cell colonization and proliferation. RT-MPs inhibited PMN formation and lung metastasis in a neutrophil- and macrophage-dependent but T cell-independent manner.