Abstract
Sema3A/NRP1 signaling promotes TAM infiltration and protumorigenic functions in hypoxic tumor areas.
Major finding: Sema3A/NRP1 signaling promotes TAM infiltration and protumorigenic functions in hypoxic tumor areas.
Concept: Sema3A-mediated localization of TAMs in distinct tumor niches determines their phenotype.
Impact: Inhibition of NRP1 on macrophages could be therapeutically useful in solid tumors.
Tumor-associated macrophages (TAM) can exhibit either pro- or antitumorigenic phenotypes. Because TAM infiltration into hypoxic areas is known to promote tumor progression, TAM phenotypes may be affected by their localization within different tumor niches. However, it is not clear how macrophages are recruited to different regions of the tumor. Seeking to determine how this process is regulated, Casazza and colleagues focused on neuropilin-1 (NRP1), a marker for proangiogenic macrophages, because previous studies indicated that blocking NRP1 signaling inhibits the growth of several different cancers. Experiments with conditional knockout mice demonstrated that macrophages lacking NRP1 could not enter hypoxic niches. Migration into these avascular regions was directed by Semaphorin-3A (Sema3A) secreted by hypoxic tumor cells, which stimulated an NRP1/PlexinA1/PlexinA4 holoreceptor to induce VEGF receptor 1 activation. In hypoxic tumor regions, stabilization of hypoxia-inducible factor 2 downregulated NRP1 expression, and Sema3A induced NRP1-independent, PlexinA1/PlexinA4-mediated inhibition of TAM migration, which allowed TAM entrapment inside the hypoxic niche. Hypoxic TAMs then became functionally polarized toward a protumorigenic “M2-like” phenotype that sustained tumor growth by promoting angiogenesis and suppressing the recruitment and proliferation of antitumorigenic Th1 T cells and cytotoxic T lymphocytes. Unlike wild-type TAMs, NRP1-deficient TAMs failed to enter the hypoxic niches and localized to normoxic regions and displayed enhanced ability to kill cancer cells, reduced proangiogenic properties, and diminished immunosuppressive capacity, which resulted in decreased tumor vascularization, restored antitumor immunity, and inhibition of tumor growth and metastasis. These data show that Sema3A/NRP1 signaling modulates TAM phenotypes, which explains why loss of NRP1 impairs tumor survival and proliferation and supports the idea that NRP1 blockade could be a useful therapeutic intervention.