Neuropilin 1: function and therapeutic potential in cancer

Abstract

Neuropilin 1 (NRP1) is a transmembrane glycoprotein that acts as a co-receptor for a number of extracellular ligands including class III/IV semaphorins, certain isoforms of vascular endothelial growth factor and transforming growth factor beta. An exact understanding of the role of NRP1 in the immune system has been obscured by the differences in NRP1 expression observed between mice and humans. In mice, NRP1 is selectively expressed on thymic-derived Tregs and greatly enhances immunosuppressive function. In humans, NRP1 is expressed on plasmacytoid dendritic cells (pDCs) where it aids in priming immune responses and on a subset of T regulatory cells (Tregs) isolated from secondary lymph nodes. Preliminary studies that show NRP1 expression on T cells confers enhanced immunosuppressive activity. However, the mechanism by which this activity is mediated remains unclear. NRP1 expression has also been identified on activated T cells and Tregs isolated from inflammatory microenvironments, suggesting NRP1 might represent a novel T cell activation marker. Of clinical interest, NRP1 may enhance Treg tumour infiltration and a decrease in NRP1+ Tregs correlates with successful chemotherapy, suggesting a specific role for NRP1 in cancer pathology. As a therapeutic target, NRP1 allows simultaneous targeting of NRP1-expressing tumour vasculature, NRP1+ Tregs and pDCs. With the development of anti-NRP1 monoclonal antibodies and cell-penetrating peptides, NRP1 represents a promising new target for cancer therapies. This paper reviews current knowledge on the role and function of NRP1 in Tregs and pDCs, both in physiological and cancer settings, as well as its potential as a therapeutic target in cancer.

MiR-148a, a microRNA upregulated in the WNT subgroup tumors, inhibits invasion and tumorigenic potential of medulloblastoma cells by targeting Neuropilin 1

“…A number of approaches have been explored for targeting NRP1 including siRNAs against NRP1, anti-NRP1 antibodies, peptides targeting NRP1, and soluble NRP1 antagonists [38, 39]. NRP1 siRNAs or anti-NRP1 peptides have been shown to inhibit tumor growth, angiogenesis and metastasis in several cancers including hepatocellular carcinoma and glioblastoma [40-42].…”

Combination cancer immunotherapy and new immunomodulatory targets

“…Neuropilin is also expressed on a subset of human T Reg cells (FIG. 3) and on a specialized subset of dendritic cells, termed plasmacytoid dendritic cells, although the functional relevance of this expression in the immune system is unclear 59,60 . Neuropilin is upregulated in multiple tumour types, and expression correlates with tumour progression 61 anti-neuropilin agent, the VEGF-specific mAb bevacizumab and chemotherapy resulted in greater than expected proteinuria 63 .…”

Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges

“…Second, VEGF inhibits DC maturation and antigen presentation, thus hampering T cell activation and, consequently, diminishing the T cell-mediated anticancer immune response 23,24 . Third, high levels of VEGF promote the recruitment and proliferation of immunosuppressive cells, including T reg cells, MDSCs, and pro-tumour, M2-like TAMs 25,26 . Fourth, VEGF promotes angiogenesis that results in an aberrant tumour vasculature, leading to hypoxia and a low pH in the TME, which in turn fosters immunosuppression both locally (FIG.…”