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.

Fig. 1

Proposed functions of NRP1 (i) In the upper figure, NRP1 couples with Plexin A and localises into the immunological synapse. This prolongs DC–T cell interaction resulting in T cell activation. In the lower figure, SEMA3A interacts with the NRP1-plexin A co-receptor complex to disrupt immunological synapse formation between DCs and NRP1+ T cells, thus inducing T cell anergy. SEMA3A also induces secretion of the immunosuppressive cytokine IL-10 (ii) NRP1 binds to VEGFR2 enhancing its affinity for VEGF. This induces NRP1+ Treg infiltration of tumours in a VEGF-directed mechanism, resulting in suppression of tumour-specific immune responses. (iii) NRP1 activates the membrane-bound LAP–TGF-β forming the active TGF-β homodimer. NRP1 also couples with TGF-βR1 and TGF-βR2 enhancing TGF-β binding. This results in direct suppression of T effector cells by membrane-bound TGF-β and conversion of NRP1 expressing CD4+ T cells into Tregs that also suppress T effector cell responses

Fig. 2

NRP1 expression enhances T cell–immature pDC interactions. Following engagement of the TCR with the MHC-peptide complex on immature pDCs, naïve NRP1− T cells do not receive the co-stimulatory signals required for T cell activation. This results in a short duration of contact between pDC and T cell that induces T cell anergy and conversion of CD4+ T cells into Tregs. NRP1 expressed on Tregs interacts homotypically with NRP1 on the immature pDC prolonging pDC–Treg interaction. The immature pDC is thus able to deliver a co-stimulatory signal resulting in Treg activation and proliferation, despite the lack of expression of co-stimulatory molecules (CD40, CD80, CD86)

Fig. 3

NRP1 as a therapeutic target. CPPs, and any co-administered molecules, nanoparticles or drugs, are internalised through the b1/b2 domain allowing selective targeting and effective penetration of NRP1-expressing tissue and cells, including tumour vasculature, NRP1+ Tregs and pDCs. mAbs specific to each extra-cellular domain of NRP1 allow specific functional blocking of NRP1 co-receptor activity: (i) Anti-MAM disrupts NRP1 homotypic interactions, preventing prolonged DC–T cell interactions. Short DC–T cell interactions induce T cell anergy and clonal deletion. (ii) Anti-b1/b2 disrupts VEGF₁₆₅ binding to NRP1, thus inhibiting VEGF-mediated NRP1+ Treg infiltration into tumours and also the angiogenic effects of VEGF. Anti-b1/b2 also inhibits TGF-β binding, thus preventing TGF-β mediated Treg generation and immune suppression. (iii) Anti-CUB inhibits SEMA3A binding to NRP1, thus preventing SEMA3A-mediated disruption of the immunological synapse and also reducing IL-10 secretion. It may also inhibit SEMA4A ligation of NRP1, thus compromising Treg stability and lineage; this has yet to be tested