Bone marrow–derived myeloid Semaphorin 4A reprograms the tumor microenvironment to foster cancer progression in pancreatic and cervical cancer

Background and aims Semaphorins (Semas) and Plexins are a family of proteins involved in the regulation of the tumor microenvironment (TME) and cancer growth. Sema4A has been recently described involved in the regulation of the immune system and tumor progression1. We previously described that Sema4A overexpressed in myeloid cells under inflammatory conditions, exerted a pro-angiogenic effect2. Herein, we investigated the role of Sema4A and its receptor in reprogramming the TME of pancreatic and cervical cancer. Methods We performed Sema4A-silenced bone marrow-derived myeloid cells (BMCs) transplantation, by means of lentiviral shRNA technology, in an orthotopic mouse model of pancreatic ductal adenocarcinoma (PDAC) and a transgenic mouse model of spontaneous multistep tumorigenesis of HPV16-induced cervical cancer (HPV16/E2) and we assessed the effect on tumor burden, metastasis and TME. Results We observed increased levels of Sema4A and its receptor PlexinB1 in PDAC and HPV16/E2 compared with normal tissues. Interestingly, we noticed that Sema4A was mainly expressed by myeloid cells and particularly by pro-tumoral M2-like macrophages. Notably, Sema4A was expressed in WT BMCs and significantly up-regulated in PDAC and HPV16/E2 BMCs. Remarkably, bone marrow transplantation of Sema4A silenced BMCs in tumor bearing PDAC and HPV16/E2 significantly hampered tumor growth e metastasis spreading. We observed that Sema4A depletion induced a shift from M2 toward M1 anti-tumor phenotype, decreased regulatory T-cells and normalized tumor vasculature in both PDAC and HPV16/E2 models. Finally, we observed that PlexinB1 inhibition in PDAC cells dramatically impaired BMC-Sema4A induced proliferation and migration. Conclusion We demonstrated that Sema4A expressed by BMCs contributes to tumor progression by acting on tumor-associated macrophages and T cells, and that its receptor PlexinB1 is mainly involved in Sema4A-induced tumor growth and invasiveness. In conclusion, Sema4A represents a novel TME biomarker for cancer progression and a new potential therapeutic target to inhibit the progression of pancreatic and cervical cancers.