Impeding Macrophage Entry into Hypoxic Tumor Areas by Sema3A/Nrp1 Signaling Blockade Inhibits Angiogenesis and Restores Antitumor Immunity

Andrea Casazza, Damya Laoui, Mathias Wenes, Sabrina Rizzolio, Nicklas Bassani, Marco Mambretti, Sofie Deschoemaeker, JoA VanGinderachter, Luca Tamagnone, Massimiliano Mazzone

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)695-709
Number of pages15
JournalCancer Cell
Volume24
Issue number6
DOIs
Publication statusPublished - Dec 9 2013

ASJC Scopus subject areas

  • Cancer Research
  • Cell Biology
  • Oncology

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