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

Menée à l'aide de modèles murins, cette étude met en évidence le rôle joué par la signalisation des protéines Sema3A et Nrp1 dans la localisation des macrophages associés aux tumeurs et leur fonction tumorigénique

Résumé en anglais

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.

"Nrp1 is required for TAM attraction toward hypoxia-induced Sema3A
"Nrp1 repression by hypoxia allows Sema-3A-mediated TAM retention in hypoxic niches
"TAM attraction needs Nrp1/VEGFR1/PlexinA1/A4 whereas TAM retention requires PlexinA1/A4
"Nrp1 deficiency excludes TAMs from hypoxic niches that favor antitumor responses