Editors' ChoiceCancer

TAMpering with the Tumor Immune Response

Sci. Signal.  17 Dec 2013:
Vol. 6, Issue 306, pp. ec307
DOI: 10.1126/scisignal.2005004

Macrophages promote the immune and inflammatory response, but tumor-associated macrophages (TAMs) infiltrating the hypoxic intratumoral area are often immunosuppressive and associated with poor prognosis. Neuropilin 1 [Nrp1, a receptor for class-3 semaphorins (Sema3)] is present on macrophages and is associated with tumor growth and angiogenesis. Using genetic tools and various mouse models, Casazza et al. identify the role of Nrp1 in mediating the protumorigenic switch in TAMs (also see Rivera and Bergers). Mice deficient for Nrp1 specifically in macrophages and their monocyte precursors (henceforth, Nrp1L/L) had smaller primary tumors, decreased tumor vessel formation, and fewer metastases compared with wild-type littermates bearing Lewis lung carcinoma (LLC) xenografts and other orthotopic or spontaneous tumors. Despite an increased number of tumor-infiltrating TAMs compared with wild-type controls, TAM accumulation in Nrp1L/L mice in all tumor models tested was primarily restricted to normoxic regions of the tumor, suggesting that Nrp1 is necessary for TAM infiltration into hypoxic regions. Endothelial cells cocultured with Nrp1L/L-isolated TAMs or grown in medium conditioned by Nrp1L/L-isolated TAMs exhibited decreased migration and branching network formation compared with those cocultured with or grown in conditioned medium from TAMs isolated from wild-type mice. Furthermore, Nrp1L/L-isolated TAMs also induced apoptosis in LLC cells in culture and stimulated proliferation of T cells in culture. In vivo, increased Nrp1L/L mice exhibited increased intratumoral infiltration of cytotoxic CD8+ T cells. The abundance of Sema3A is increased in hypoxic tumors. Consistent with Sema3A functioning as the attractant for TAMs to the hypoxic region of tumors, Nrp1L/L-isolated TAMs in culture did not migrate in response to Sema3A; in vivo, TAM infiltration of Sema3A-containing matrigel plugs was decreased in Nrp1L/L mice, and knock-in mice containing TAMs expressing a mutant Nrp1 that could not bind Sema3A did not have TAM infiltration into the hypoxic tumor region. However, TAMs isolated from hypoxic LLC tumor regions in wild-type mice had nearly undetectable expression of Nrp1 compared with those in normoxic regions, and genetic inactivation studies in macrophages indicated that hypoxia induced transcriptional repression of Nrp1 by the transcription factor NF-κB. Thus, Sema3a appeared to recruit the TAMs to the hypoxic region of the tumor through Nrp1, after which the cells underwent a transcription-mediated switch and this promigratory pathway was inhibited. Sema3A can also stimulate vascular endothelial growth factor receptor 1 (VEGFR1) and Plexins to inhibit chemotaxis. In situ binding experiments showed that Sema3A bound Nrp1L/L-TAMs, and investigation of the response in cultured TAMs showed that this was mediated by VEGFR1 and Plexin A1 and A4. Together, the findings suggest that Sema3A initially attracts TAMs to the hypoxic tumor regions through its interaction with Nrp1, upon which they undergo a protumorigenic switch. Thus, blocking Nrp1 in macrophages may prevent their recruitment and their protumorigenic effects.

A. Casazza, D. Laoui, M. Wenes, S. Rizzolio, N. Bassani, M. Mambretti, S. Deschoemaeker, J. A. Van Ginderachter, L. Tamagnone, M. Mazzone, Impeding macrophage entry into hypoxic tumor areas by Sema3A/Nrp1 signaling blockade inhibits angiogenesis and restores antitumor immunity. Cancer Cell 24, 695–709 (2013). [Online Journal]

L. B. Rivera, G. Bergers, Location, location, location: Macrophage positioning within tumors determines pro- or antitumor activity. Cancer Cell 24, 687–689 (2013). [Online Journal]

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