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.

Neuropilin-1 mediates myeloid cell chemoattraction and influences retinal neuroimmune crosstalk

“…ROCK is downstream of NRP-1 signaling (42) and is known to mediate monocyte migration (43). VEGF migration was partially yet not significantly diminished, suggesting a contribution from alternate receptors such as VEGFR1 as recently reported (33). Consistent with a role for NRP-1 in SEMA3A-and VEGF-mediated chemotaxis, macrophages from LysM-Cre …”

“…Neuropilin-1 mediates myeloid cell chemoattraction and influences retinal neuroimmune crosstalk described on microglia during vascular anastomosis (31) and recently described in tumor-associated macrophages with roles in vessel maturation (32) and proangiogenic properties (33). Importantly, the physiological role of myeloid-resident NRP-1 remains unclear, particularly in the context of the CNS.…”

Antibody Blockade of Semaphorin 4D Promotes Immune Infiltration into Tumor and Enhances Response to Other Immunomodulatory Therapies

“…For example, associations of Sema3a and Neuropilin-1 have been reported to regulate movement of tumor-associated macrophages (TAM) in hypoxic regions (11). Herein, we describe a novel role for the regulation of leukocyte infiltration and tumor growth by semaphorin 4D (SEMA4D, CD100).…”

Ly6Clo monocytes drive immunosuppression and confer resistance to anti-VEGFR2 cancer therapy

“…To date, 10 anti-VEGF drugs have been approved by the FDA to treat various solid tumors, starting with metastatic colorectal cancer (CRC) in 2004 (1). However, the survival benefit from these drugs is modest, as tumors develop resistance to these agents (3,4,(6)(7)(8)(9)(10)(11)(12)(13). The mechanisms of resistance remain far from understood.…”

“…The immune microenvironment has drawn great interest for its strong influence on tumor growth (7,8,10,12,(14)(15)(16)(17)(18)(19)(20)(21)(22). Emerging data show that the immune system also plays a critical role in refractoriness to antiangiogenic therapy (13,23,24).…”