Deletion of Neuropilin 1 from Microglia or Bone Marrow–Derived Macrophages Slows Glioma Progression

Abstract

Glioma-associated microglia and macrophages (GAM), which infiltrate high-grade gilomas, constitute a major cellular component of these lesions. GAM behavior is influenced by tumor-derived cytokines that suppress initial antitumorigenic properties, causing them to support tumor growth and to convert and suppress adaptive immune responses to the tumor. Mice that lack the transmembrane receptor neuropilin-1 (Nrp1), which modulates GAM immune polarization, exhibit a decrease in glioma volumes and neoangiogenesis and an increase in antitumorigenic GAM infiltrate. Here we show that replacing the peripheral macrophage populations of wild-type mice with Nrp1-depleted bone marrow-derived macrophages (BMDM) confers resistance to the development of glioma. This resistance occurred in a similar fashion seen in mice in which all macrophages lacked Nrp1 expression. Tumors had decreased volumes, decreased vascularity, increased CTL infiltrate, and Nrp1-depleted BMDM adopted a more antitumorigenic phenotype relative to wild-type GAMs within the tumors. Mice with Nrp1-deficient microglia and wild-type peripheral macrophages showed resistance to glioma development and had higher microglial infiltrate than mice with wild-type GAMs. Our findings show how manipulating Nrp1 in either peripheral macrophages or microglia reprograms their phenotype and their pathogenic roles in tumor neovascularization and immunosuppression. This study highlights the proangiogenic receptor neuropilin 1 in macrophages and microglial cells in gliomas as a pivotal modifier of tumor neovascularization and immunosuppression, strengthening emerging evidence of the functional coordination of these two fundamental traits of cancer. .

Expression of neuropilin-1 is linked to glioma associated microglia and macrophages and correlates with unfavorable prognosis in high grade gliomas

“…Our present comprehensive analysis of NRP1 expression in human GB, in combination with the conclusions from our murine glioma model [ 20 , 21 , 23 ], suggest that NRP1 is a valid target to pursue in future work. The observed correlation with genes characteristic of pro-tumorigenic GAMs, and the high cellular fractions found in the TME also suggest that there is a strong connection between NRP1 and tumor supporting cell populations.…”

“…Based on our animal data [ 20 , 21 , 23 ], we sought to make meaningful extrapolations about NRP1 expression in human glioma. TCGA database enabled the mining of publicly available data before embarking on large scale human projects.…”

“…This process regulates the expression of VEGF, contributes to vascular remodeling, and is reportedly dependent on the activity of hypoxia-inducible factor 1-alpha (Hif1a) [ 19 , 29 , 42 , 45 ]. We have previously shown that NRP1-deficient bone marrow-derived monocytes that traffic to the TME exhibit a large decrease in expression of Hif1a [ 21 ]. This finding is recapitulated in human GB, where NRP1 was found to be highly correlated with Hif1a expression (Figure 6 ).…”

“…Our lab has previously shown that GAM-specific ablation of NRP1, or global pharmacological inhibition of this co-receptor, slows tumor progression in a mouse model of GB, in a similar fashion, by inhibiting neoangiogenesis and reducing immunosuppressive signaling [ 20 ]. Further, we reported that either population of microglia or peripheral macrophages lacking NRP1 were sufficient to inhibit disease progression in this model [ 21 ]. We have also shown qualitatively that NRP1 co-localizes with the pan-monocyte marker Iba1 across all glioma grades in archived human biopsies [ 20 ].…”

Current insights into matrix metalloproteinases and glioma progression: transcending the degradation boundary

“…Recent extensive reviews, including therapeutic approaches targeting microglia, are explained by Roesch et al 165 and Hambardzumyan et al 166 Recent work has sought to dissect further the pathological molecular mechanisms behind VEGF receptor-TGFβ receptor complex activities, 167 and indeed it has been shown that neuropilin 1 is a critical coreceptor in the induction of GAMs in a mouse model of glioma. 168 Furthermore, GAMs are thought to contribute to the poor efficacy of some oncolytic viruses by sequestering and inhibiting the replication of the therapeutic virus. 169 Specific to MMPs, the hypoxic environment characteristic of high-grade gliomas is known to induce MMP expression, and macrophages can independently induce MMP9 expression from glioma cells, with a slight additive effect in a hypoxic setting.…”