Targeting neuropilin-1 with nanobodies reduces colorectal carcinoma development

Yannick De Vlaeminck, Stefano Bonelli, Robin Maximilian Awad, Maarten Dewilde, Sabrina Rizzolio, Quentin Lecocq, Evangelia Bolli, Ana Rita Santos, Damya Laoui, Steve Schoonooghe, Luca Tamagnone, Cleo Goyvaerts, Massimiliano Mazzone, Karine Breckpot, Jo A. Van Ginderachter

Research output: Contribution to journalArticlepeer-review

Abstract

Neuropilin-1 (NRP-1) is a co-receptor for semaphorins and vascular endothelial growth factor (VEGF) family members that can be expressed on cancer cells and tumor-infiltrating myeloid, endothelial and lymphoid cells. It has been linked to a tumor-promoting environment upon interaction with semaphorin 3A (Sema3A). Nanobodies (Nbs) targeting NRP-1 were generated for their potential to hamper the NRP-1/Sema3A interaction and their impact on colorectal carcinoma (CRC) development was evaluated in vivo through the generation of anti-NRP-1-producing CRC cells. We observed that tumor growth was significantly delayed and survival prolonged when the anti-NRP-1 Nbs were produced in vivo. We further analyzed the tumor microenvironment and observed that the pro-inflammatory MHC-IIhigh/trophic MHC-IIlow macrophage ratio was increased in tumors that produce anti-NRP-1 Nbs. This finding was corroborated by an increase in the expression of genes associated with MHC-IIhigh macrophages and a decrease in the expression of MHC-IIlow macrophage-associated genes in the macrophage pool sorted from anti-NRP-1 Nb-producing tumors. Moreover, we observed a significantly higher percentage of tumor-associated antigen-specific CD8+ T cells in tumors producing anti-NRP-1 Nbs. These data demonstrate that an intratumoral expression of NRP-1/Sema3A blocking biologicals increases anti-tumor immunity.

Original languageEnglish
Article number3582
Pages (from-to)1-21
Number of pages21
JournalCancers
Volume12
Issue number12
DOIs
Publication statusPublished - Dec 2020

Keywords

  • Cancer
  • Immune checkpoint
  • Immunotherapy
  • Nanobody
  • Neuropilin-1
  • Plexin
  • Semaphorin
  • Single-domain antibody fragment
  • Tumor-associated macrophage

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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