Tumor-derived exosomes favor immunosuppression and metastatic spread by acting on myeloid cells

It is widely recognized that the immune system can be highly affected by tumors through a plethora of mechanisms that allow avoiding an efficient recognition and eradication of cancer cells. Among these mechanisms, tumor secretome, including tumor-derived soluble factors (TDSFs) and, more recently, extracellular vesicles (EVs), is currently drawing much attention in the immune-oncology field. Particularly, by interacting either with stromal or other tumor cells, tumor-derived exosomes (TEX) have been demonstrated as key regulators in cancer development, as well as on the metastatic process. Since myeloid-derived suppressor cells (MDSCs) are critical contributors to the aforementioned processes, we investigated the TEX-MDSCs interaction, highlighting the main functional consequences of this crosstalk. Indeed, we could demonstrate a TEX-mediated effect on MDSC suppressive functions, which was even more striking in the case of bone-marrow naïve monocytes. Furthermore, we demonstrated that this is mainly mediated by iNOS engagement on myeloid cells, possibly induced by molecules enriched within TEX. In addition, the injection of TEX derived from high metastatic cancer cells in naïve tumor-free mice before the tumor challenge with a low metastatic cell line induced an increased spread of cancer cells in the lungs of TEX-treated mice. In the attempt to dampen TEX detrimental effects in tumor models, we blocked exosome secretion through GW4869 drug administration, which did not ameliorate the spread of metastatic cells. On the contrary, by targeting one of the TEX-downstream mediators, i.e. a member of the S100 proteins family, tumor-bearing mice displayed a restrained suppressive tumor network and a strong reduction in the metastatic incidence. Finally, we demonstrated that S100A8/A9 sera levels negatively correlated with distant metastasis-free survival in pancreatic ductal adenocarcinoma (PDAC) patients. In conclusion, our preliminary data highlighted the urgency of developing novel and more effective therapeutic approaches based on a full characterization of TEX-induced pathways in myeloid cells within the local tumor milieu and, moreover, at distal sites of metastasis