How do tumor-associated neutrophils regulate the microenvironmental landscape of brain tumors: Delivery of nano-particles through BBB.

Glioblastoma multiforme (GBM) is the most aggressive form of brain cancer with the very poor survival and high recurrence rate. Tumor-associated neutrophils (TANs) play a pivotal role in regulation of the tumor microenvironment. In this study, we developed a new mathematical model of the critical GBM-TAN interaction in the heterogeneous brain tissue. The model reveals that the dual and complex role of TANs (either anti-tumorigenic N1 and the pro-tumorigenic N2 type) regulates the phenotypic trajectory of the evolution of tumor growth and the invasive patterns in white and gray matter via mediators such as IFN-β and TGF-β. We investigated the effect of normalizing the immune environment on glioma growth by applying a therapeutic antibody and developed several strategies for eradication of tumor cells by neutrophil-mediated transport of nanoparticles. We also developed a strategy of combination therapy (surgery + Trojan neutrophils) for effective control of the infiltration of the glioma cells in one hemisphere before crossing the corpus callosum (CC) in order to prevent recurrence in the other hemisphere. This alternative approach compared to the extended resection of the glioma including CC or butterfly GBM may provide the greater anti-tumor efficacy and reduce side effects such as cognitive impairment.