Inhibition of Semaphorin 4A-expressing bone marrow-derived myeloid cells impairs tumor progression in PDAC

Semaphorins (Semas) and Plexins belong to a large protein family of axon guidance cues involved in the regulation of tumor progression, metastasis spreading and tumor microenvironment (TME). Among these, Sema4A is critically involved in the regulation of the immune response, but its role in cancer progression is still unclear. In the present study, we investigated the role of Sema4A and its receptors in the progression of pancreatic ductal adenocarcinoma (PDAC). Herein we showed that Sema4A was highly expressed by myeloid cells and particularly by pro-tumoral M2 macrophages in the stroma of PDAC compared with the normal pancreas. Interestingly, Sema4A was produced by bone marrow-derived (BM) myeloid cells in wild type mice and its expression strongly increases during tumor progression. Stemming from these findings, in the attempt to assess the functional role of Sema4A on myeloid cells and tumor progression, we efficiently silenced Sema4A in BM cells by means of lentiviral shRNA technology. Notably, one month after transplantation of BM-derived myeloid cells silenced for Sema4A in previously irradiated (7 Gy) PDAC mice, hampered tumor growth and Liver metastasis formation. We also observed a dramatic reduction of M2 macrophages, decrease of regulatory T cells and an induction of vessel normalization in Sema4A-silenced PDAC tumors. Interestingly, recombinant Sema4A promoted proliferation, migration and invasiveness of PDAC cells and the depletion of Sema4A receptor PlexinB1, reverted these effects, suggesting a cross-talk among Sema4A-expressing myeloid cells and PlxinB1/b2-expressind PDAC cells during tumor progression. In conclusion, our findings demonstrate that Sema4A expressed by BMCs contributes to tumor progression by acting on tumor-associated macrophages, T cells, and that its receptor PlexinB1 identifying Sema4A as both a novel biomarker for cancer progression and a potential therapeutic target to inhibit pancreatic cancer growth.