Neuropilins, as Relevant Oncology Target: Their Role in the Tumoral Microenvironment

Abstract

Angiogenesis is one of the key mechanisms involved in tumor growth and metastatic dissemination. The vascular endothelial growth factor (VEGF) and its receptors (VEGFR) represent one of the major signaling pathways which mediates angiogenesis. The VEGF/VEGFR axis was intensively targeted by monoclonal antibodies or by tyrosine kinase inhibitors to destroy the tumor vascular network. By inhibiting oxygen and nutrient supply, this strategy was supposed to cure cancers. However, despite a lengthening of the progression free survival in several types of tumors including colon, lung, breast, kidney, and ovarian cancers, modest improvements in overall survival were reported. Anti-angiogenic therapies targeting VEGF/VEGFR are still used in colon and ovarian cancer and remain reference treatments for renal cell carcinoma. Although the concept of inhibiting angiogenesis remains relevant, new targets need to be discovered to improve the therapeutic index of anti-VEGF/VEGFR. Neuropilin 1 and 2 (NRP1/2), initially described as neuronal receptors, stimulate angiogenesis, lymphangiogenesis and immune tolerance. Moreover, overexpression of NRPs in several tumors is synonymous of patients' shorter survival. This article aims to overview the different roles of NRPs in cells constituting the tumor microenvironment to highlight the therapeutic relevance of their targeting.

Keywords: cancers; immunology; neuropilins; oncology; tumor microenvironment.

FIGURE 1

Role of NRPs in the activation or suppression of the immune system. (A) NRP1 homophilic interaction enhances the interaction between naive cytotoxic T cells and dendritic cells inducing a prolonged antigen presentation and so T cell activation. (B) Expression of SEMA3A by mature cytotoxic T cells inhibits NRP1 localisation and induces T cell anergy. (C) Interaction between NRP1, expressed by Treg cells, with SEMA4A, expressed by dendritic cells maintain Treg functions. (D) Interaction between NRP1, expressed by Treg cells, with VEGF, expressed by tumor cells, enable Treg cells infiltration into the tumor and induce an immunosuppression. (E) NRP1+ helper T cells induce B cells differentiation to activate their immune response. (F) Interaction between NRP1, expressed by macrophages, with SEMA3A, expressed by tumor cells, induce the formation of tumor associated macrophages (TAM) and so a tumor progression.