title: Impeding macrophage entry into hypoxic tumor areas by Sema3A/Nrp1 signaling blockade inhibits angiogenesis and restores antitumor immunity.
abstract: Recruitment of tumor-associated macrophages (TAMs) into avascular areas sustains tumor progression; however, the underlying guidance mechanisms are unknown. Here, we report that hypoxia-induced Semaphorin 3A (Sema3A) acts as an attractant for TAMs by triggering vascular endothelial growth factor receptor 1 phosphorylation through the associated holoreceptor, composed of Neuropilin-1 (Nrp1) and PlexinA1/PlexinA4. Importantly, whereas Nrp1 levels are downregulated in the hypoxic environment, Sema3A continues to regulate TAMs in an Nrp1-independent manner by eliciting PlexinA1/PlexinA4-mediated stop signals, which retain them inside the hypoxic niche. Consistently, gene deletion of Nrp1 in macrophages favors TAMs' entrapment in normoxic tumor regions, which abates their pro-angiogenic and immunosuppressive functions, hence inhibiting tumor growth and metastasis. This study shows that TAMs' heterogeneity depends on their localization, which is tightly controlled by Sema3A/Nrp1 signaling.
authors: Laboratory of Molecular Oncology and Angiogenesis, Vesalius Research Center, VIB, 3000 Leuven, Belgium; Laboratory of Molecular Oncology and Angiogenesis, Department of Oncology, Vesalius Research Center, KU Leuven, 3000 Leuven, Belgium.
authors: Andrea
authors: A
authors: Casazza
authors: Laboratory of Myeloid Cell Immunology, VIB, 1050 Brussels, Belgium; Laboratory of Cellular and Molecular Immunology, Department of Molecular and Cellular Interactions, Vrije Universiteit Brussel, 1050 Brussels, Belgium.
authors: Damya
authors: D
authors: Laoui
authors: Laboratory of Molecular Oncology and Angiogenesis, Vesalius Research Center, VIB, 3000 Leuven, Belgium; Laboratory of Molecular Oncology and Angiogenesis, Department of Oncology, Vesalius Research Center, KU Leuven, 3000 Leuven, Belgium.
authors: Mathias
authors: M
authors: Wenes
authors: Institute for Cancer Research at Candiolo, Department of Oncology, University of Torino, 10060 Candiolo, Torino, Italy.
authors: Sabrina
authors: S
authors: Rizzolio
authors: Laboratory of Molecular Oncology and Angiogenesis, Vesalius Research Center, VIB, 3000 Leuven, Belgium; Laboratory of Molecular Oncology and Angiogenesis, Department of Oncology, Vesalius Research Center, KU Leuven, 3000 Leuven, Belgium.
authors: Nicklas
authors: N
authors: Bassani
authors: Laboratory of Molecular Oncology and Angiogenesis, Vesalius Research Center, VIB, 3000 Leuven, Belgium; Laboratory of Molecular Oncology and Angiogenesis, Department of Oncology, Vesalius Research Center, KU Leuven, 3000 Leuven, Belgium.
authors: Marco
authors: M
authors: Mambretti
authors: Laboratory of Molecular Oncology and Angiogenesis, Vesalius Research Center, VIB, 3000 Leuven, Belgium; Laboratory of Molecular Oncology and Angiogenesis, Department of Oncology, Vesalius Research Center, KU Leuven, 3000 Leuven, Belgium.
authors: Sofie
authors: S
authors: Deschoemaeker
authors: Laboratory of Myeloid Cell Immunology, VIB, 1050 Brussels, Belgium; Laboratory of Cellular and Molecular Immunology, Department of Molecular and Cellular Interactions, Vrije Universiteit Brussel, 1050 Brussels, Belgium.
authors: Jo A
authors: JA
authors: Van Ginderachter
authors: Institute for Cancer Research at Candiolo, Department of Oncology, University of Torino, 10060 Candiolo, Torino, Italy.
authors: Luca
authors: L
authors: Tamagnone
authors: Laboratory of Molecular Oncology and Angiogenesis, Vesalius Research Center, VIB, 3000 Leuven, Belgium; Laboratory of Molecular Oncology and Angiogenesis, Department of Oncology, Vesalius Research Center, KU Leuven, 3000 Leuven, Belgium. Electronic address: massimiliano.mazzone@vib-kuleuven.be.
authors: Massimiliano
authors: M
authors: Mazzone
mesh_terms: D000818:Animals; D015687:Cell Hypoxia; D008264:Macrophages / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009374:Neoplasms, Experimental / Q000098:blood supply* / Q000276:immunology / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D039942:Neuropilin-1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D040121:Semaphorin-3A / Q000037:antagonists & inhibitors / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: C488217:Sema3a protein, mouse; D040121:Semaphorin-3A; D039942:Neuropilin-1