The Role of Neuropilin in Microglia during Glioma Progression

Abstract

Malignant gliomas are the most commonly diagnosed tumors of the central nervous system (CNS). Despite management, median time of survival after diagnosis falls between 12 to 15 months. Current treatment modalities are suboptimal and there is a substantial need to develop more effective therapies. Modulation of the immune system is a promising strategy as innate and adaptive immunity play important roles in cancer progression. Neuropilin 1 (Nrp1), is responsible for amplifying pro‐angiogenic signaling within the tumor microenvironment and its expression correlates with glioma malignancy. Nrp1 also signals via additional pathways and plays a role in the behavior of innate immune cells. Microglia, the resident macrophages of the CNS, can comprise over 30% of the cells in glioma biopsies. Gliomas secrete cytokines which suppress the anti‐tumorigenicity of microglia, causing them to secrete factors that support the tumor's spread and growth. Some of the factors which are secreted by gliomas in high amounts signal via Nrp1 and its co‐receptors. The objective of this research is to identify how Nrp1‐mediated signaling in microglia affects glioma progression. Using a Cre‐lox system, we generated mice which lack expression of Nrp1 in microglia and macrophages (MG/MPs). We demonstrate in an in vivo orthotopic glioma model, that tumors exhibit less vascularity, grow at a slower pace, and are populated by MG/MPs which exhibit a more anti‐tumorigenic phenotype in mice that lack Nrp1 in MG/MPs or that are treated with a small molecule inhibitor of Nrp1. We conclude that ablation or pharmacologic inhibition of Nrp1 promotes an anti‐tumorigenic shift in the phenotype of MG/MPs, effectively reducing tumor growth.