Chemotherapeutic Tumor Microparticles Elicit a Neutrophil Response Targeting Malignant Pleural Effusions
Pingwei Xu, Ke Tang, Jingwei Ma, Huafeng Zhang, Dianheng Wang, Liyan Zhu, Jie Chen, Keke Wei, Jincheng Liu, Haiqing Fang, Liang Tang, Yi Zhang, Jing Xie, Yuying Liu, Rui Meng, Li Liu, Xiaorong Dong, Kunyu Yang, Gang Wu, Fei Ma, Bo Huang
Abstract
Abstract Malignant pleural effusion (MPE) is a frequent complication of various cancers and often leads to a poor quality of life, prognosis, and life expectancy, and its management remains palliative. New approaches that can effectively treat MPE are highly desirable. Here, we show that methotrexate (MTX)-packaging tumor cell–derived microparticles (MTX-MP) act as an effective immunotherapeutic agent to treat patients with MPE by mobilizing and activating neutrophils. We find that MTX-MP perfusion via a pleural catheter elicits the recruitment of neutrophils in patients through macrophage-released CXCL1 and CXCL2. By performing ex vivo experiments, we find that the recruited neutrophils are activated and release reactive oxygen species (ROS) and neutrophil extracellular trap (NET) to kill tumor cells. Neutrophil-released NETs were also able to seal off the damaged endothelium, facilitating MPE resolution in vitro and in tumor-bearing mice. These findings reveal the potential for use of cell-derived materials to package drugs as an immunotherapeutic agent against MPE.